Characterization of novel p53 and FA/BRCA pathway mutations from children with cancer

1 PhD project offered in the IPP winter call 2020/2021

Scientific Background

Dysfunction of the DNA damage response and DNA repair is a driving force for genome instability and cancer. In childhood cancers, inherited mutations in cancer predisposition genes substantially contribute to cancer development. Childhood cancer is frequently linked to specific cancer-predisposing syndromes (CPS) including Li-Fraumeni syndrome (LFS), Li-Fraumeni like syndrome (LFLS) and Fanconi anemia (FA)/BRCA. Whereas LFS and LFLS patients are characterized by germline mutations deregulating the tumor suppressor p53 pathway, FA/BRCA patients usually harbor mutations in genes regulating DNA double-strand break (DSB) repair. Using whole-exome sequencing (WES) of father, mother and children trios we have identified novel heterozygous germline mutations in genes regulating the p53 and FA/BRCA pathway in children with cancer. Understanding the molecular function of these novel mutations will provide important insight in the development of childhood cancer and might contribute to novel treatment options. 

PhD project proposal: Characterization of novel p53 and FA/BRCA pathway mutations from children with cancer

This project aims at elucidating the molecular functions and the biological effects of the novel germline mutations identified in the p53 and FA/BRCA pathway. The highly motivated candidate will be educated in a broad spectrum of techniques from molecular biology, biochemistry, cell biology to molecular genetics to characterize the novel p53 & FA/BRCA pathway mutations The functional and mechanistic consequences of the identified mutations will be analyzed by using protein-protein interaction and interactome/mass spectrometry analysis, confocal microscopy, p53 target gene analysis (RNA Seq), FACS-based cell cycle/cell death assays, DNA repair assays and genomic instability analysis.

Publications relevant to the project

Kuhlen M, Taeubner J, Brozou T, Wieczorek D, Siebert R and Borckhardt A. (2019) Family-based germline sequencing in children with cancer. Oncogene 38:1367-1380.

Bitomsky N, Conrad E, Moritz C, Polonio-Vallon T, Sombroek S, Schultheiss C, Glas C, Greiner V, Herbel C, Mantovani F, del Sal G, Peri F, Hofmann TG (2013). Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc Natl Acad Sci USA 110: 115-25.
 
Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J, Hofmann TG (2008) Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature Cell Biology 10:812-824.

Contact Details

Prof. Thomas Hofmann

Universitätsmedizin Mainz
Gebäude 905/4. OG
Obere Zahlbacher Str. 67
D-55131 Mainz
Germany