Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) Promotes Non-homologous End Joining and Inhibits Homologous Recombination Repair upon DNA Damage

Background: The role of SMCHD1 in DNA damage response is largely unknown. Results: SMCHD1 recruitment to DNA damage foci is regulated by 53BP1. Knocking out SMCHD1 compromised cell survival, and decreased the efficiency of non-homologous end joining (NHEJ) while elevating the efficiency of homologous recombination (HR). Conclusion: SMCHD1 regulates both NHEJ and HR. Significance: Our findings should further understanding of how cells adopt different repair pathways. Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) has been shown to be involved in gene silencing and DNA damage. However, the exact mechanisms of how SMCHD1 participates in DNA damage remains largely unknown. Here we present evidence that SMCHD1 recruitment to DNA damage foci is regulated by 53BP1. Knocking out SMCHD1 led to aberrant H2AX foci accumulation and compromised cell survival upon DNA damage, demonstrating the critical role of SMCHD1 in DNA damage repair. Following DNA damage induction, SMCHD1 depletion resulted in reduced 53BP1 foci and increased BRCA1 foci, as well as less efficient non-homologous end joining (NHEJ) and elevated levels of homologous recombination (HR). Taken together, these results suggest an important function of SMCHD1 in promoting NHEJ and repressing HR repair in response to DNA damage.