Consequences of DNA damage induced chromatin changes in spermatozoa and damage repair in zygotes

• Applicants: Professor Dr. Björn Schumacher; Dr. Siyao Wang, Ph.D.
• Subject Area: Reproductive Medicine, Urology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561031107

The male germline is the source of 80% of inheritable mutations in humans. The control of genome stability in the paternal germline is inferior to the maternal germline. Spermatozoa are particularly vulnerable to DNA damage. The highly compacted genome structure and the single copy of the genome limits the recognition and repair of damage. However, genomically compromised spermatozoa are completely proficient in fertilization resulting in inheritable DNA damage. Using the C. elegans model we recently established that DNA damage in spermatozoa is inaccurately repaired by maternal Theta-mediated endjoining (TMEJ). TMEJ was only recently discovered and was originally thought to serve as a backup double strand break repair mechanism. Our work, however, established TMEJ as the major route of zygotic DNA repair of paternal DNA damage. TMEJ causes structural variants (SVs) that consequently give rise to recurrent DNA damage presumable via the breakage-fusion-bridge cycle. We identified similar TMEJ products as the predominant type of paternally inherited SVs in humans indicating that the consequence of inaccurate zygotic repair might play a major role in the generation of human germline mutations. The overarching goal of this proposal is to establish the mechanisms of the DNA damage response in spermatozoa and based on our previous results in C. elegans, establish the degree of evolutionary conservation of mechanisms in mammals. We propose to specifically (1) Decipher the mechanism of blockage of double strand break repair in spermatozoa, (2) Define the chromatin structure changes in spermatozoa upon DNA damage and identify their mechanisms of action, and (3) Dissect how the chromatin changes in spermatozoa influence the consequent repair in the zygote. This highly ambitious proposal aims to break new grounds in the understanding of germline mutagenesis and how limitation of the DNA damage response in spermatozoa underlies the vulnerability of the paternal genome. The combined expertise of the DNA repair expert Schumacher, the epigenetics expert Wang and the mammalian germ cell expert Klutstein allow a highly complementary research program exploring mechanisms in the C. elegans model and in the mouse system.

• DFG Programme: Research Grants
• International Connection: Israel
• Partner Organisation: The Israel Science Foundation
• Cooperation Partner: Professor Dr. Michael Klutstein, Ph.D.