RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

Renier Vélez-Cruz, Swarnalatha Manickavinayaham, Anup K. Biswas, Regina Weaks Clary, Tolkappiyan Premkumar, Francesca Cole, David G. Johnson

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss.

Original languageEnglish (US)
Pages (from-to)2500-2512
Number of pages13
JournalGenes and Development
Volume30
Issue number22
DOIs
StatePublished - Nov 15 2016

Keywords

  • BRG1
  • DNA end resection
  • E2F1
  • Homologous recombination
  • Retinoblastoma
  • SWI/SNF

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

MD Anderson CCSG core facilities

  • Genetically Engineered Mouse Facility
  • Research Animal Support Facility
  • Science Park Flow Cytometry

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