CHK2 regulates MUS81-dependent DSBs in response to replication stress and BRCA2 deficiency.

CHK2-dependent phosphorylation of MUS81 promotes DSB formation during replication stress, crucial for fork recovery in BRCA2-deficient human cells.

• Why it matters: Understanding how MUS81 is regulated during replication stress is vital because its misregulation can lead to genome instability, especially in cells lacking BRCA2, which are prone to cancer.
• What they did: The study used cellular and biochemical approaches to show CHK2 binds to the MUS81-EME2 complex via FHA domain, with phosphorylation at S95 and S97 regulating its activity and interaction with SLX4 during S-phase.
• The result: This regulatory mechanism enables MUS81 to process stalled or deprotected forks, facilitating fork recovery and cell viability, and highlights a new role for the ATM-CHK2 pathway in maintaining genome stability under replication stress.