Widespread chromatin context dependencies of DNA repair
Event details
| Date | 10.04.2025 |
| Hour | 09:30 › 10:30 |
| Speaker | Xabier Vergara, The Netherlands Cancer Institute |
| Location |
SV 1717
|
| Category | Conferences - Seminars |
| Event Language | English |
Abstract:
DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. Examples of the latter are the FANC complex and ATM. Moreover, in a diversity of human cancer types, the loss of several of these proteins, including ATM, alters the distribution of pathway-specific mutations between heterochromatin and euchromatin. To further investigate the role of DNA repair proteins in heterochromatin, we used pA-DamID to map genome-nuclear lamina (NL) interactions during the DSB repair process. These experiments revealed that NL interactions around the DSB are temporarily disrupted over several megabases, which is dependent on gH2AX and ATM. Together, these results uncover a complex network of proteins that regulate DNA repair pathway balance in a chromatin context-dependent manner.
DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. Examples of the latter are the FANC complex and ATM. Moreover, in a diversity of human cancer types, the loss of several of these proteins, including ATM, alters the distribution of pathway-specific mutations between heterochromatin and euchromatin. To further investigate the role of DNA repair proteins in heterochromatin, we used pA-DamID to map genome-nuclear lamina (NL) interactions during the DSB repair process. These experiments revealed that NL interactions around the DSB are temporarily disrupted over several megabases, which is dependent on gH2AX and ATM. Together, these results uncover a complex network of proteins that regulate DNA repair pathway balance in a chromatin context-dependent manner.
Practical information
- General public
- Free
Organizer
- Prof. Bart Deplancke
Contact
- joanna.rusnok@epfl.ch