BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure

Haijuan Yang, Philip D. Jeffrey, Julie Miller, Elspeth Kinnucan, Yutong Sun, Nicolas H. Thomä, Ning Zheng, Phang Lang Chen, Wen Hwa Lee, Nikola P. Pavletich

Research output: Contribution to journalArticlepeer-review

579 Scopus citations

Abstract

Mutations in the BRCA2 (breast cancer susceptibility gene 2) tumor suppressor lead to chromosomal instability due to defects in the repair of double-strand DNA breaks (DSBs) by homologous recombination, but BRCA2's role in this process has been unclear. Here, we present the 3.1 angstrom crystal structure of a ∼90-kilodalton BRCA2 domain bound to DSS1, which reveals three oligonucleotide-binding (OB) folds and a helix-turn-helix (HTH) motif. We also (i) demonstrate that this BRCA2 domain binds single-stranded DNA, (ii) present its 3.5 angstrom structure bound to oligo(dT)9′ (iii) provide data that implicate the HTH motif in dsDNA binding, and (iv) show that BRCA2 stimulates RAD51-mediated recombination in vitro. These findings establish that BRCA2 functions directly in homologous recombination and provide a structural and biochemical basis for understanding the loss of recombination-mediated DSB repair in BRCA2-associated cancers.

Original languageEnglish (US)
Pages (from-to)1837-1848
Number of pages12
JournalScience
Volume297
Issue number5588
DOIs
StatePublished - Sep 13 2002
Externally publishedYes

ASJC Scopus subject areas

  • General

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