JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1–mediated chromatin response to DNA breaks

Although the DNA damage–induced ubiquitylation by RNF8 and/or RNF168 ubiquitin ligases is crucial for the DNA-damage response (DDR), the precise mechanisms of ubiquitylation-mediated chromatin modulation and recruitment of DNA-repair proteins 53BP1 and RAP80–BRCA1 are not fully understood. A new study now indicates that human demethylase JMJD1C regulates the RAP80–BRCA1 branch of this DDR pathway. Chromatin ubiquitylation flanking DNA double-strand breaks (DSBs), mediated by RNF8 and RNF168 ubiquitin ligases, orchestrates a two-branch pathway, recruiting repair factors 53BP1 or the RAP80–BRCA1 complex. We report that human demethylase JMJD1C regulates the RAP80–BRCA1 branch of this DNA-damage response (DDR) pathway. JMJD1C was stabilized by interaction with RNF8, was recruited to DSBs, and was required for local ubiquitylations and recruitment of RAP80–BRCA1 but not 53BP1. JMJD1C bound to RNF8 and MDC1, and demethylated MDC1 at Lys45, thereby promoting MDC1-RNF8 interaction, RNF8-dependent MDC1 ubiquitylation and recruitment of RAP80–BRCA1 to polyubiquitylated MDC1. Furthermore, JMJD1C restricted formation of RAD51 repair foci, and JMJD1C depletion caused resistance to ionizing radiation and PARP inhibitors, phenotypes relevant to aberrant loss of JMJD1C in subsets of breast carcinomas. These findings identify JMJD1C as a DDR component, with implications for genome-integrity maintenance, tumorigenesis and cancer treatment.