JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks.
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.
1] Danish Cancer Society Research Center, Copenhagen, Denmark. [2] [3].
Sugiko
S
Watanabe
Kenji
K
Watanabe
Vyacheslav
V
Akimov
Jirina
J
Bartkova
Blagoy
B
Blagoev
Jiri
J
Lukas
Jiri
J
Bartek
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D018797:Cell Cycle Proteins; D053960:DNA Breaks; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C486521:RNF8 protein, human; D015534:Trans-Activators; C466234:UIMC1 protein, human; C520448:JMJD1C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D010089:Oxidoreductases, N-Demethylating; D044767:Ubiquitin-Protein Ligases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase