RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1

Shinichiro Nakada, Rikako Miyamoto Yonamine, Koichi Matsuo

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The tumor suppressor protein BRCA1 localizes to sites of DNA double-strand breaks (DSB), promoting repair by homologous recombination through the recruitment of DNA damage repair proteins. In normal cells, homologous recombination largely depends on BRCA1. However, assembly of the pivotal homologous recombination regulator RAD51 can occur independently of BRCA1 in the absence of 53BP1, another DNA damage response protein. How this assembly process proceeds is unclear, but important to understand in tumor cell settings where BRCA1 is disabled. Here we report that RNF8 regulates BRCA1-independent homologous recombination in 53BP1-depleted cells. RNF8 depletion suppressed the recruitment of RAD51 to DSB sites without affecting assembly or phosphorylation of the replication protein RPA in neocarzinostatin-treated or X-ray-irradiated BRCA1/53BP1-depleted cells. Furthermore, RNF8/BRCA1/53BP1-depleted cells exhibited less efficient homologous recombination than BRCA1/53BP1-depleted cells. Intriguingly, neither RNF8 nor its relative RNF168 were required for RAD51 assembly at DSB sites in 53BP1-expressing cells. Moreover, RNF8-independent RAD51 assembly was found to be regulated by BRCA1. Together, our findings indicate a tripartite regulation of homologous recombination by RNF8, BRCA1, and 53BP1. In addition, our results predict that RNF8 inhibition may be a useful treatment of BRCA1-mutated/53BP1low cancers, which are considered resistant to treatment by PARP1 inhibitors and of marked current clinical interest.

Original languageEnglish
Pages (from-to)4974-4983
Number of pages10
JournalCancer Research
Volume72
Issue number19
DOIs
Publication statusPublished - 2012 Oct 1

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Double-Stranded DNA Breaks
Homologous Recombination
DNA Damage
Zinostatin
Tumor Suppressor Proteins
Recombinational DNA Repair
Proteins
DNA Repair
Neoplasms
Phosphorylation
X-Rays

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1. / Nakada, Shinichiro; Yonamine, Rikako Miyamoto; Matsuo, Koichi.

In: Cancer Research, Vol. 72, No. 19, 01.10.2012, p. 4974-4983.

Research output: Contribution to journalArticle

Nakada, Shinichiro ; Yonamine, Rikako Miyamoto ; Matsuo, Koichi. / RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1. In: Cancer Research. 2012 ; Vol. 72, No. 19. pp. 4974-4983.
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