PRESS RELEASE

14 December – Scientists at the Institute of Molecular Biology (IMB) and Mainz University in Germany may have discovered new insights into how cancer cells regulate the ends of their chromosomes, called telomeres. Certain cancers use a specific type of telomere regulation called ALT, which was thought to allow them to become immortal. Prof. Brian Luke and his group found that ALT cells may actually undergo senescence, which could mean that they are vulnerable to drugs designed to kill senescent cells. This finding could open the way for new therapies to slow or stop ALT cancer cells from growing.

Cancer remains one of the biggest killers and is among the hardest diseases to treat. The root cause of all cancers is the uncontrolled growth of cancer cells, which multiply rapidly until they form large tumours that spread throughout the body, causing sickness and even death. The reason why cancer cells grow so quickly is in part due to their ability to lengthen the ends of their DNA, which are called telomeres.

When normal, healthy cells divide, the ends of their chromosomes get shorter with each division. Eventually, they get so short that the cell detects a problem and stops dividing. This halt in cell division is called replicative senescence and is an important safety mechanism that prevents cells from becoming cancerous.

Cancer cells, however, manage to find ways to circumvent this by lengthening their telomeres, preventing them from shortening. This allows them to keep dividing and proliferate beyond the normal limit, effectively becoming immortal. Most cancers do this by activating a factor called telomerase, which adds more telomeric DNA to the ends of chromosomes, while about 15% of cancers activate an alternative mechanism called ALT (Alternative Lengthening of Telomeres), where the cell uses its own existing telomeres as a template to make more copies of telomeric DNA.

Previously, scientists thought that ALT allowed cancer cells to become immortal – i.e. that they could grow and divide forever. However, Prof. Luke’s lab at the University of Mainz now find in their most recent study, which was published in Nucleic Acids Research, that this is not the case. His lab uses baker’s yeast to study how ALT works. “Under certain conditions, yeast cells can lengthen their telomeres in a manner nearly identical to ALT cancer cells; we call them ALT yeast,” he explains. Stefano Misino, a former PhD student in Prof. Luke’s lab, says “We discovered that ALT yeast only appear immortal if we grow them as a mixed population of cells with different telomere lengths. However, when we isolated and grew ALT yeast cells individually, we could clearly see that they started to grow slower and slower after multiple cell divisions”. They saw that the telomeres in these individual ALT yeast cells also became shorter over time.

This indicates that cells that maintain their telomeres with ALT still undergo replicative senescence, and they may in fact not be immortal. This is an exciting finding because if ALT cancer cells do undergo senescence, they could be treated using new drugs that specifically kill senescent cells.

In addition, Prof. Luke and his team found that an RNA molecule called TERRA, which is made at telomeres, can control the rate of senescence in ALT yeast cells and appears to affect how quickly telomeres shorten. He is hopeful that these new findings will pave the way for new strategies to treat cancer. “If we can figure out a way to manipulate the RNA, we could increase the rates of senescence in these ALT cells to slow down or even stop their growth.”

^{The image above shows trees (which represent telomeres) on rolling hills (representing the senescence curves). At the bottom of the first curve, the cells hit a low point of proliferative potential, however they recover and form ALT survivors. Thanks to the findings in this paper, we now know that these cells also start going down the hill again, losing telomere length and replicative potential. Illustration generated with the AI software DALL-E and Photoshop.}

^{Further details}

^{Further information can be found at https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac1125/6885047}

^{Brian Luke is a Professor at the University of Mainz and an Adjunct Scientific Director at the Institute of Molecular Biology. Further information about research in the Luke lab can be found at: https://www.imb.de/research/luke/research}

^{About the Institute of Molecular Biology gGmbH}

^{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on three cutting-edge areas: epigenetics, developmental biology, and genome stability. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de}

^{Boehringer Ingelheim Foundation}

^{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de}  

^{Press contact for further information}

^{Dr Ralf Dahm, Director of Scientific Management}

^{Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128 Mainz, Germany}

^{Phone: +49 (0) 6131 39 21455, Email: press@imb.de}

JOINT PRESS RELEASE OF IMB AND JGU

25 November - The German Research Foundation (DFG) announced the prolongation of the Collaborative Research Centre (CRC) 1361: "Regulation of DNA Repair and Genome Stability" for an additional four years. The consortium was established in 2019 at Johannes Gutenberg University Mainz (JGU) in collaboration with the Institute of Molecular Biology Mainz (IMB), the Technical University of Darmstadt, Goethe University Frankfurt, and Ludwig Maximilian University Munich. It comprises 18 research projects, three technology platforms and an integrated graduate program. It aims to elucidate the mechanisms by which cells safeguard their genetic information. As deficiencies in genome maintenance result in a variety of disorders including cancer and accelerated ageing, a better understanding of DNA repair is key to promoting human health.

During its first funding period, the CRC 1361 made groundbreaking advances in characterising the components of DNA repair and DNA damage signalling pathways that act as decision-makers in the regulation of genome maintenance. Structural studies have provided insight into the mechanisms of DNA damage signalling at DNA double-strand breaks, and genomic approaches have revealed the origins of oncogenic chromosome aberrations resulting from such lesions. Overall, the research has highlighted the relevance of endogenous factors as sources of genome instability.

Enhanced focus on systems-wide aspects of DNA repair

In its second four-year funding period, the CRC will receive approximately €10.6 million to deepen its mechanistic analysis of genome maintenance systems and intensify its efforts to draw functional connections between individual repair pathways in order to integrate them into larger regulatory networks. This will involve enhanced systems-level approaches to determine the genome-wide distribution of lesions. The researchers will focus their investigation primarily on various endogenous sources of genome instability, how they are perceived by cellular signalling pathways and processed by dedicated or overlapping DNA repair pathways, and their implications for cell fate.

Prof. Helle Ulrich, a Scientific Director at IMB, Professor in the Faculty of Biology of Mainz University and the CRC's spokesperson, is excited about the DFG's decision to continue funding the CRC. "Over the past four years, we have managed to establish a highly collaborative environment for our research", she says. "Our enhanced focus on systems-wide aspects of DNA repair will now allow us to tackle even more ambitious questions about how these important cellular surveillance systems act in a physiological context."

Consolidation of Mainz as a hub of genome stability research

With its focus on genome stability, the CRC complements and strengthens ongoing research activities in Mainz and the Rhine-Main area in fields ranging from RNA biology, epigenetics and gene regulation to protein homeostasis and quality control. Prof. Stefan Müller-Stach, JGU's Vice President for Research and Early Career Academics, comments: "The interdisciplinary nature of the CRC contributes to the consolidation of Mainz as a hub of genome stability research and ensures a high-quality education for the next generation of scientists in the field." He sees the CRC as a critical pillar in the emerging priority area of ageing, senescence and longevity research in Mainz, a crosscutting initiative that unites fundamental biological science with clinical and applied research in cancer, immunology, neurobiology and human physiology.

Successful Rhine-Main Universities collaboration

The continued funding of CRC 1361 is also a great success for the strategic alliance of the Rhine-Main Universities (RMU), formed by Goethe University Frankfurt, Johannes Gutenberg University Mainz and the Technical University of Darmstadt. As outstanding research universities having collaborated with each other for many years, they joined together to form the strategic RMU alliance in 2015 to promote strong collaboration in science and research, offer joint degree programs for their students and to strengthen knowledge transfer and exchange with society and business.

The DFG's funding of CRCs supports long-term research collaborations lasting up to 12 years in which scientists work together within the framework of an interdisciplinary research program. The aim is to create an institutional focus by working on innovative, demanding, complex and long-term research projects through the coordination and concentration of people and resources in the applicant universities.

^{For more information on the CRC 1361, please visit www.sfb1361.de}

^{About the Institute of Molecular Biology gGmbH (IMB)
The Institute of Molecular Biology gGmbH (IMB) is a center of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing, and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed EUR 154 million to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately EUR 50 million for the construction of a state-of-the-art building and is giving a further EUR 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de}

^{About Johannes Gutenberg University Mainz
Johannes Gutenberg University Mainz (JGU) is a globally recognized research-driven university with around 31,000 students from over 120 nations. Its core research areas are in particle and hadron physics, the materials sciences, and translational medicine. JGU's success in Germany's Excellence Strategy program has confirmed its academic excellence: In 2018, the research network PRISMA+ (Precision Physics, Fundamental Interactions and Structure of Matter) was recognized as a Cluster of Excellence – building on its forerunner, PRISMA. Moreover, excellent placings in national and international rankings as well as numerous honors and awards demonstrate the research and teaching quality of Mainz-based researchers and academics. For more information about Mainz University, please visit: www.uni-mainz.de/eng}

^{Boehringer Ingelheim Foundation
The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. For more information about the Boehringer Ingelheim Foundation, please visit: www.bistiftung.de}

<sup>Press contact for further information:
Dr Ralf Dahm
Director of Scientific Management
Institute of Molecular Biology gGmbH (IMB)
Ackermannweg 4, 55128 Mainz, GERMANY

phone: +49 6131 39-21455
email: press@imb.de</sup>

PRESS RELEASE

25 November - The German Research Foundation (DFG) has announced the funding of the Collaborative Research Centre (CRC) 1551 on “Polymer Concepts in Cellular Function”. This research initiative will be funded for an initial 4 years and will be established at Johannes Gutenberg University Mainz (JGU) in collaboration with the Institute of Molecular Biology Mainz (IMB) and the Max Planck Institute of Polymer Research. Researchers in the CRC 1551 will apply theoretical and experimental polymer science concepts such as protein disorder, super-selectivity, multi-component and also fundamental polymer properties like phase separation to biological research questions, thereby opening new ways to understand cellular function, as well as dysfunction in ageing and disease processes.

The CRC 1551 is spearheaded by Prof. Edward Lemke, who is a Professor of Synthetic Biophysics of Protein Disorder at JGU and an Adjunct Director at IMB. Prof. Lemke considers the establishment of this new CRC to be a milestone for Mainz and Germany. “The CRC will become an interdisciplinary think tank where polymer scientists and life scientists come together to study the polymer properties of DNA, RNA and proteins to better understand how the interplay between these biopolymers govern key cellular functions, as well as how it drives cellular dysfunction and ageing. For this purpose, we have put together outstanding teams of researchers from the fields of the life sciences and polymer research”. In total, the DFG will provide ~ €10 million for the funding of the CRC 1551 in its first funding period.

The new CRC will bring together polymer scientists and molecular life scientists from JGU, IMB, the Max Planck Institute for Polymer Research and UMC in 13 research projects, with 4 supportive service projects. “We will study how biopolymers, including DNA, RNA and disordered proteins, form higher-order complexes or organelles and how they interact to regulate key cellular processes, such as transcription or splicing. In particular, we want to understand how disordered protein regions encode molecular function, but also how aberrant interactions between disordered regions can lead to protein aggregation and neurodegenerative disorders”, says Prof. Dorothee Dormann, Professor of Molecular Cell Biology at JGU, Adjunct Director at IMB and vice spokesperson of the CRC. Thus, the research of CRC 1551 will help scientists gain a better understanding of how cells age on the molecular level and could provide a basis for the development of a new generation of therapeutics.

^{Further details}

^{Edward Lemke is an Adjunct Director at IMB and a Professor of Synthetic Biophysics at Johannes Gutenberg University Mainz. Further information about research in Lemke lab can be found at www.imb.de/lemke and www.lemkelab.com.}

^{Dorothee Dormann is Adjunct Director at IMB and a Professor of Molecular Cell Biology at Johannes Gutenberg University Mainz. Further information about research in the Dormann lab can be found at www.imb.de/dormann.}

^{About the Institute of Molecular Biology gGmbH}

^{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de.}

^{About Johannes Gutenberg University Mainz}

^{Johannes Gutenberg University Mainz (JGU) is a globally recognized research-driven university with around 31,000 students from over 120 nations. Its core research areas are in particle and hadron physics, the materials sciences, and translational medicine. JGU's success in Germany's Excellence Strategy program has confirmed its academic excellence: In 2018, the research network PRISMA+ (Precision Physics, Fundamental Interactions and Structure of Matter) was recognized as a Cluster of Excellence – building on its forerunner, PRISMA. Moreover, excellent placings in national and international rankings as well as numerous honors and awards demonstrate the research and teaching quality of Mainz-based researchers and academics. Further information at www.uni-mainz.de/eng}

^{Boehringer Ingelheim Foundation}

^{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de}

^{Press contact for further information}

^{Dr Ralf Dahm, Director of Scientific Management}

^{Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128 Mainz, Germany}

^{Phone: +49 (0) 6131 39 21455, Email: press@imb.de}

PRESS RELEASE 

22 November – The Institute of Molecular Biology (IMB), Johannes Gutenberg University Mainz (JGU) and its University Medical Center (UMC) will receive funding for the second phase of their joint research project, the " Science of Healthy Ageing Research Programme” (SHARP).

The SHARP project aims to investigate the molecular causes underlying the ageing process and thus makes important contributions to our understanding of ageing and its associated diseases, such as dementia and cardiovascular disease. As human life expectancy steadily increases, the development of treatments and therapies that enable healthy ageing and promote the best possible quality of life is becoming increasingly important.

Last week, Science Minister Clemens Hoch presented a state grant of €1.56 million to the SHARP partners. The first phase of the project has now been successfully completed and the second phase is scheduled to run until the end of 2025. "Funding of this joint project on ageing between IMB, Mainz University and its University Medical Center represents an important step towards strengthening the national and international position of our medical and life science leaders. Furthermore, it positions Mainz as an internationally visible beacon in the field of ageing research." Clemens Hoch continued: "The high performance of our research landscape was visibly demonstrated by the development of the COVID-19 vaccine by BioNTech/Pfizer. Such scientific findings are the result of years of research at JGU and UMC, and constitute a central starting point for important scientific developments. Cooperation with industry – such as the non-profit company TRON GmbH in the case of vaccine development – is essential for maximising the chances of success. This is a particularly impressive demonstration that sustainable research funding by the state is bearing fruit that benefits society as a whole."

"Beyond the scientific knowledge gained, SHARP creates an important bridge between basic molecular research at IMB and clinical research at UMC," said the Vice President for Research and Young Scientists at JGU, Prof. Dr Stefan Müller-Stach. "We are pleased that the state government continues to support our strengths in ageing research with this clear commitment to scientific excellence."

"We are very pleased to receive this continued funding. The SHARP funding helps us build a better network between physicians and basic scientists," said Prof. Dr René Ketting, Executive Director of IMB. "This in turn makes it possible for us to tailor research to better match the health and needs of ageing patients."

"SHARP is an important step in securing the innovative capacity of Mainz as a centre of science and research through the targeted integration of doctoral students in our highest-performing groups in ageing research. We have already established an elaborate selection procedure in the first funding phase to bring together bright and motivated minds. They will now take on the challenge of finding new perspectives for preventing and treating age-related diseases in our ageing society. The interdisciplinary SHARP programme is complemented by both specific and general training courses for the students and thus makes an important contribution to ensuring the future viability of our institute, even beyond our own location and the funding period of the SHARP project. We are therefore very grateful for the state of Rhineland-Palatinate’s consistent support of ageing research", says Prof. Dr Hansjörg Schild, Deputy Scientific Director and Vice-Dean for Research at UMC.

The SHARP partners are key players in the biotechnology landscape of Rhineland-Palatinate, which the state government intends to expand consistently over the next few years. The state of Rhineland-Palatinate plans to continue the strong promotion of life science research and invest at least €100 million over the next 10 years. This is to be doubled through federal and private funding. A further €10 million will follow for new priority investments in the current legislative period.

Background information on SHARP:

The Science of Healthy Ageing Research Programme (SHARP) project aims to strengthen collaboration between basic molecular biology research groups at IMB and preclinical and clinical research groups at UMC. Funding is provided for projects in which basic researchers work directly with patient-oriented researchers. Combining the expertise of basic researchers and clinically-oriented scientists leads to a faster application of results from basic research and ensures that the treatment of patients at the University Medical Center is in line with the latest medical research.

Additional networking will be achieved by recruiting doctoral students for collaborative projects on the "Biology of Ageing", which will be jointly supervised by IMB and UMC. SHARP therefore combines the strengths of research on the molecular mechanisms underlying ageing with research on age-associated diseases. In this way, SHARP will bring together a broad expertise to make new discoveries on the key molecular mechanisms underlying ageing and how cutting-edge technologies can be applied to treat age-related diseases. This breadth and depth will contribute to significant advances in ageing research, which will translate into clinically applicable approaches for patients. Mainz is ideally positioned as a science location for the establishment of SHARP, as there are already a significant number of basic and clinical researchers active in a broad range of key areas in ageing research.

_{Further details}

_{Further information can be found here.}

_{About the Institute of Molecular Biology gGmbH}

_{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit www.imb.de.}

_{About the Centre for Healthy Ageing}

_{The Centre for Healthy Ageing (CHA) is a virtual research centre launched in 2021 that brings together scientists in basic and clinical research from across Mainz that focus on ageing and age-related diseases. These findings should be used to promote healthy ageing and to find treatments that could prevent or cure age-related disease. For more information, please visit: www.cha-mainz.de.}

_{About the MWG:}

_{The Ministry of Science and Health (MWG) represents the departments of Science and Health within the Rhineland-Palatinate state government. This includes medical care in the state, as well as the areas of universities and research. Rhineland-Palatinate is a state of innovation. In expanding science and technological development, the state's numerous coordinated measures focus specifically on key areas of growth. Through this, it succeeds in improving the scientific competitiveness of universities, expanding research infrastructure, attracting more top researchers and intensifying the transfer of knowledge between science and industry. The state government also wants all citizens to have the same access to high-quality, affordable medical and nursing care, regardless of whether they live in a city or a rural region in Rhineland-Palatinate. It therefore promotes the systematic networking of outpatient and inpatient care, as well as new treatment concepts and innovative medical products.}

_{About Johannes Gutenberg University Mainz}

_{Johannes Gutenberg University Mainz (JGU) is a globally recognised research-driven university with around 31,000 students from over 120 nations. Its core research areas are in particle and hadron physics, the materials sciences, and translational medicine. JGU's success in Germany's Excellence Strategy programme has confirmed its academic excellence: In 2018, the research network PRISMA⁺ (Precision Physics, Fundamental Interactions and Structure of Matter) was recognised as a Cluster of Excellence – building on its forerunner, PRISMA. Moreover, excellent placings in national and international rankings as well as numerous honours and awards demonstrate the research and teaching quality of Mainz-based researchers and academics. Further information at www.uni-mainz.de/eng}

_{Boehringer Ingelheim Foundation}

_{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de}

_{Press contact for further information}

_{Dr Ralf Dahm, Director of Scientific Management}

_{Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128 Mainz, Germany}

_{Phone: +49 (0) 6131 39 21455, Email: press@imb.de}

_{Susanne Gellweiler, Press Officer}

_{Ministry of Science and Health (MWG), Mittlere Bleiche 61, 55116 Mainz, Germany}

_{Phone: +49 6131 16 2839, Email: susanne.gellweiler@mwg.rlp.de}

RESEARCH HIGHLIGHTS 

18 November – The group of Dr Julian König at the Institute of Molecular Biology (IMB) has mapped ~200 mutations that clinicians could use to predict whether patients with B-cell acute lymphoblastic leukaemia will respond to immunotherapy. This work was performed in collaboration with the labs of Kathi Zarnack (Goethe University Frankfurt) and Stephan Legewie (University of Stuttgart) and was published in the journal Nature Communications.

B-cell acute lymphoblastic leukaemia (B-ALL) is an aggressive cancer that affects both children and adults. It is the most common cancer in children and remains a leading cause of death. B-ALL specifically affects B-cells, which are a type of white blood cell. One treatment for B-ALL is to teach the body how to recognise and kill these malignant B-cells using CART-19 therapy, which is a type of immunotherapy. In CART-19 therapy, the patient’s own natural cytotoxic immune cells, called T-cells, are engineered to target a surface antigen protein called CD19, which is specifically found on B-cells. This leads the body’s immune system to attack the cancerous B-cells and can be highly effective.

However, a major problem is that in many patients, the cancerous B-cells eventually stop expressing CD19, or only produce a shortened version of CD19, so that they are no longer targeted by the engineered T-cells. This is commonly caused by mutations that alter the splicing of the CD19 mRNA. When this happens, CART-19 therapy is no longer effective, the cancer reappears and patients relapse. Previous studies show that over 50% of B-ALL patients can relapse, despite initial success with CART-19 therapy.

Currently, it is not possible to tell which patients may relapse. Studies show that some B-ALL patients may have CD19 splicing mutations even before CART-19 therapy, which could indicate that they are more likely to relapse. Therefore, it would be highly useful to identify patients without these pre-existing mutations, as they are more likely to benefit from CART-19 therapy and less likely to relapse. However, cancer cells typically have hundreds, if not thousands, of different mutations, and it is extremely difficult to determine which particular mutations alter CD19 splicing.

To identify all the mutations that could affect CD19 splicing, Julian and his colleagues applied an ambitious new strategy: they used high-throughput mutagenesis to create 10,295 mutant CD19 minigenes (comprising CD19 exons 1, 2 and 3 and their introns), each with an average of 9.7 mutations. They then sequenced the mRNAs produced by these mutant genes to identify those with abnormal splicing. Using mathematical modelling to analyse the entire dataset, they identified 193 point mutations that significantly altered CD19 splicing. Overlapping these mutations with the predicted binding sites of RNA-binding proteins also allowed the researchers to identify 119 RNA-binding proteins that may be responsible for regulating CD19 splicing.  

This new high-throughput strategy is much more effective than previous methods because it allowed them to obtain a complete picture of how splicing is regulated at CD19, not just the effects of a few select mutations. Clinical researchers can now use this information to identify patients with mutations that may result in a higher chance of CART-19 therapy relapse. Julian, a co-corresponding author of the study, says “We found many more CD19 mutations and proteins that affect splicing than were previously recognised, suggesting that CD19 splicing is regulated by an extensive network of RNA-binding proteins. In future, we hope to use this information to develop new treatments using splicing modulators that could be used in combination with other therapies to limit cancer relapse and resistance to therapy.”

_{Further details}

_{Further information can be found at https://www.nature.com/articles/s41467-022-31818-y}

_{Julian König is a Group Leader at the Institute of Molecular Biology (IMB). Further information about research in König lab can be found at www.imb.de/koenig}

_{About the Institute of Molecular Biology gGmbH}

_{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de.}

_{Boehringer Ingelheim Foundation}

_{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de}

_{Press contact for further information}

_{Dr Ralf Dahm, Director of Scientific Management}

_{Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128 Mainz, Germany}

_{Phone: +49 (0) 6131 39 21455, Email: press@imb.de}

RESEARCH HIGHLIGHTS

07 November – The research group of Prof. Christof Niehrs at the Institute of Molecular Biology (IMB) has discovered a new chemical modification of mammalian DNA called adenine poly-ADP-ribosylation. This discovery adds a surprisingly bulky base modification to the known repertoire of enzyme-catalysed DNA modifications in mammals.

The master instructions of a cell are found in its DNA, which encodes all the information necessary for it to function properly. DNA contains four bases – adenine, thymine, guanine and cytosine (A, T, G and C) – which are like the letters used to write the ‘instructions’. Some of these bases can also be enzymatically modified by the addition of chemical groups, which can act as markers on the DNA to alter gene expression. For example, the base cytosine can be modified into methylcytosine by the addition of a methyl group, which is a marker of transcriptional silence.

ADP-ribosylation is a chemical modification known to occur on proteins, either as a single ADP group (mono-ADP-ribosylation) or a chain of ADP groups (poly-ADP-ribosylation, or PARylation) and is catalysed by the PARP family of ADP-ribose polymerases. However, no one knew whether these modifications occurred in mammalian DNA.

In this study, which was published in Nature Communications, Christof and his group set out for a closer look at this possibility. They first confirmed the presence of PARylation in mouse and human DNA using antibodies against ADP and mass spectrometry, painstakingly excluding all other potential sources of PARylation (such as proteins and RNA). They then proved that reducing expression of the enzyme PARP1 decreased DNA PARylation, while inhibition of another enzyme (PAR glycohydrolases) increased the amount of DNA PARylation. This is important because it argues that DNA PARylation is added or removed from DNA by enzymes in the cell as part of a biological pathway (and not by spontaneous non-enzymatic reactions or DNA damage).

Now that they knew mammalian DNA could be PARylated, the researchers wanted to know where in the genome it occurred. Using in vitro and mass spectrometry studies, they found that PARP1 catalyses PARylation on single-stranded but not double-stranded DNA, and that the modification is added to the base adenine.

The discovery of a previously unknown DNA base modification is extremely important because it could lead to the discovery of new epigenetic processes. “We were excited when we realised we were dealing with an unknown DNA base modification. The major challenge was to pinpoint the identity of this DNA modification down to the chemical linkage between the base and the polymer. We initially couldn’t make sense of the parameters we got from the mass spectrometer. But luckily it finally sunk in”, says Lars Schomacher, co-first and co-corresponding author of the study.

The most important step now is to identify the role of adenine PARylation in the cell. The researchers initially thought that adenine PARylation might be involved in the repair of DNA breaks, but did not find evidence to support this. As the modification only occurs at very low frequencies in mammalian DNA (the researchers calculated there were ~1-2 PARylation sites per genome), the researchers speculate that it might occur transiently in specific circumstances when one strand of DNA is exposed and accessible for PARylation. Lars says, “We are far from concluding that adenine PARylation is an important regulatory mark. Such a bulky base modification seems to be rather incompatible with essential cellular processes like DNA replication or transcription. But because we found it under physiological conditions and it is generated by an important cellular enzyme, we believe it has its function.”

_{Further details}

_{Further information can be found at https://www.nature.com/articles/s41467-022-33731-w}

_{Christof Niehrs is a Scientific Director at the Institute of Molecular Biology (IMB). Further information about research in Niehrs lab can be found at www.imb.de/niehrs.}

_{About the Institute of Molecular Biology gGmbH}

_{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de.}

_{Boehringer Ingelheim Foundation}

_{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de}

_{Press contact for further information}

_{Dr Ralf Dahm, Director of Scientific Management}

_{Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128 Mainz, Germany}

_{Phone: +49 (0) 6131 39 21455, Email: press@imb.de}

PRESS RELEASE

07 October – The Institute of Molecular Biology (IMB) is pleased to announce that Dr Malene Hansen will be joining its Scientific Advisory Board (SAB). Malene is a Professor and Chief Scientific Officer at the Buck Institute for Research on Aging in Novato, California, USA. She is a global leader in the field of ageing research and is deeply committed to the education and mentoring of junior scientists.

Prof. Malene Hansen’s research focuses on cellular autophagy, a homeostatic process by which cells remove and recycle misfolded or damaged proteins. This is extremely important for maintaining cell function and organismal health. Autophagy is thought to be a key mechanism of ageing, as many organisms show decreased autophagy with age. Moreover, perturbed autophagy is often seen in age-related diseases such as cancer, diabetes and neurodegenerative disease.  

Malene’s lab focuses on understanding how autophagy declines with ageing, and the underlying genes that regulate these changes. Her work is the first step towards the discovery of new treatments to treat age-related diseases, extend human lifespan and promote healthy ageing.

Malene’s extensive expertise in ageing research will be an invaluable addition to IMB's SAB. The SAB is comprised of seven internationally renowned researchers, who visit IMB every 1-2 years to review its achievements and provide advice and recommendations on the institute’s strategic research directions and management, as well as recruitment and career development programmes for junior scientists. We welcome Prof. Hansen to our SAB and look forward to receiving her advice and guidance.

_{Further details}

_{Further information can be found at https://www.buckinstitute.org/lab/hansen-lab}

_{About the Institute of Molecular Biology gGmbH}

_{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de.}

_{Boehringer Ingelheim Foundation}

_{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de}

_{Press contact for further information}

_{Dr Ralf Dahm, Director of Scientific Management}

_{Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128 Mainz, Germany}

_{Phone: +49 (0) 6131 39 21455, Email: press@imb.de}

PRESS RELEASE

20 September – Dr Sara Vieira-Silva has been awarded the Antoine Faes Prize for her postdoctoral research on the role of the human gut microbiome in health and disease. Sara joined the Institute of Molecular Biology (IMB) as an Adjunct Group Leader this year and is also a Group Leader at the University Medical Center of Johannes Gutenberg University Mainz.

The Antoine Faes Prize is awarded every three years by the Antoine Faes Foundation to support biomedical research in Belgium with a positive societal impact. The winners were selected by an international jury of leading experts. This year, the winning research theme was “Microbiology: good and bad micro-organisms”. The prize was jointly awarded to Prof. Sarah Lebeer (University of Antwerp, Belgium) and Prof. Jeroen Raes, Dr Gwen Falony and Dr Vieira-Silva (KU Leuven, Belgium).

Sara’s research focuses on microorganisms that live in the human gut. When these gut microbe populations are disrupted (e.g. by changes in diet), they can contribute to diseases such as obesity, diabetes, cardiovascular disease or ageing by promoting inflammation or producing carcinogens and endocrine disruptors. The Antoine Faes prize recognises Dr Vieira-Silva’s work on the Flemish Gut Flora Project at the Catholic University in Leuven (KU Leuven), Belgium, where she worked for the last 8 years as a postdoctoral researcher in the lab of Prof. Jeroen Raes. For this project, she studied gut microbe samples from more than 3,000 individuals to understand natural variation in the human microbiome and its metabolic contribution to human health.

The results of the study, which were published in two articles in the journal Science in 2016 and Nature Microbiology in 2019, revealed that humans have at least four distinct patterns of gut microbes and that one of these is associated with inflammatory diseases. More recently, Sara and her collaborators showed that lipid-lowering drugs called statins may restore disturbed gut microbiome profiles in obesity-associated low-grade inflammation, opening future opportunities for new therapeutic treatments (published in the journal Nature in 2021).

We warmly congratulate Sara on receiving the Antoine Faes Prize.

^{Further details}

^{Sara Vieira-Silva is an Adjunct Group Leader at IMB and a Group Leader the University Medical Center of Johannes Gutenberg University Mainz. Further information about research in Vieira-Silva lab can be found at www.imb.de/vieira-silva.}

^{About the Institute of Molecular Biology gGmbH}

^{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de.}

^{About Johannes Gutenberg University Mainz}

^{Johannes Gutenberg University Mainz (JGU) is a globally recognized research-driven university with around 31,000 students from over 120 nations. Its core research areas are in particle and hadron physics, the materials sciences, and translational medicine. JGU's success in Germany's Excellence Strategy program has confirmed its academic excellence: In 2018, the research network PRISMA+ (Precision Physics, Fundamental Interactions and Structure of Matter) was recognized as a Cluster of Excellence – building on its forerunner, PRISMA. Moreover, excellent placings in national and international rankings as well as numerous honors and awards demonstrate the research and teaching quality of Mainz-based researchers and academics. Further information at www.uni-mainz.de/eng}

^{Boehringer Ingelheim Foundation}

^{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its Perspectives Programme Plus 3 and its Exploration Grants, the Foundation supports independent junior group leaders. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB), the department of life sciences at the University of Mainz, and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.bistiftung.de}

^{Press contact for further information}

^{Dr Ralf Dahm, Director of Scientific Management}

^{Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, 55128 Mainz, Germany}

^{Phone: +49 (0) 6131 39 21455, Email: press@imb.de}