Projects Offered

1 PhD project offered in the IPP winter call Molecular Mechanisms in Genome Stability & Gene Regulation

Scientific Background

DNA damage poses a significant threat to genome stability, chromosomal integrity, and cellular function. Transcription-coupled nucleotide excision repair (TC-NER) defects can cause growth and mental retardation, photosensitivity, and premature aging in Cockayne syndrome (CS) patients. Chromatin serves as a platform for DNA repair and undergoes dynamic changes during the DNA damage response (DDR) through the Access-Repair-Restore model. Histones, an essential component of chromatin, are post-translationally modified via methylation, ubiquitination, and acetylation to regulate DDR-related chromatin functions. Many histone modifications leave long-term epigenetic memory in cells and can be transmitted across generations, raising the possibility that DNA damage can reshape the epigenome in damaged cells and affect their descendants.

Due to the complexity of human epigenetics, we used C. elegans as a model to study the role of histone modifications on genome stability, longevity, and transgenerational inheritance.

PhD Project: Transgenerational epigenetic memory of paternal DNA damage

The transgenerational effect of DNA damage has been previously studied through epidemiological and genetic approaches, but these have yielded contradictory results. Recently, we identified a novel mechanism that underlies the transgenerational genetic and epigenetic effects of paternal DNA damage. Using sex-separated C. elegans strains, we found that paternal, but not maternal, exposure to ionizing radiation (IR) leads to transgenerational embryonic lethality. This lethality is caused by the persistence of DNA double-strand breaks (DSBs) in the F1 generation, where a highly enriched heterochromatin structure blocks the accessibility of homologous recombination (HR) repair machinery. This project will investigate how DNA damage in sperm alters the epigenome of the offspring, and whether these changes in the epigenome can affect genome stability and longevity of the subsequent generations. Via answering these questions, we aim to identify potential therapeutic approaches to improve the genome stability of the worms carrying paternally inherited DNA DSBs.

If you are interested in this project, please select Wang as your group preference in the IPP application platform.

Publications relevant to this project

Wang S, Meyer DH & Schumacher B (2023) Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature 613, 365–374 Link

Panier S, Wang S, Schumacher B (2023) Genome instability and DNA repair in somatic and reproductive aging. Annu Rev Pathol19, 261-290 Link