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gamma H2A binds Brc1 to maintain genome integrity during S-phase

Academic Article
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Overview

authors

  • Williams, J. S.
  • Williams, R. S.
  • Dovey, C. L.
  • Guenther, G.
  • Tainer, John
  • Russell, Paul

publication date

  • March 2010

journal

  • EMBO Journal  Journal

abstract

  • ATM(Tel1) and ATR(Rad3) checkpoint kinases phosphorylate the C-terminus of histone H2AX (H2A in yeasts) in chromatin flanking DNA damage, establishing a recruitment platform for checkpoint and repair proteins. Phospho-H2A/X (gammaH2A/X)-binding proteins at double-strand breaks (DSBs) have been characterized, but those required for replication stress responses are unknown. Here, we present genetic, biochemical, small angle X-ray scattering (SAXS), and X-ray structural studies of the Schizosaccharomyces pombe Brc1, a 6-BRCT-domain protein that is structurally related to Saccharomyces cerevisiae Rtt107 and mammalian PTIP. Brc1 binds gammaH2A to form spontaneous and DNA damage-induced nuclear foci. Spontaneous Brc1 foci colocalize with ribosomal DNA repeats, a region prone to fork pausing and genomic instability, whereas DNA damage-induced Brc1 foci colocalize with DSB response factors. gammaH2A binding is critical for Brc1 function. The 1.45 A resolution crystal structure of Brc1-gammaH2A complex shows how variable BRCT insertion loops sculpt tandem-BRCT phosphoprotein-binding pockets to facilitate unique phosphoprotein-interaction specificities, and unveils an acidic DNA-mimicking Brc1 surface. From these results, Brc1 docking to gammaH2A emerges as a critical chromatin-specific response to replication-associated DNA damage.

subject areas

  • Crystallography, X-Ray
  • DNA Damage
  • Histones
  • Models, Molecular
  • Protein Conformation
  • S Phase
  • Schizosaccharomyces
  • Schizosaccharomyces pombe Proteins
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Research

keywords

  • DNA replication
  • Schizosaccharomyces pombe
  • X-ray crystal structure
  • chromatin
  • genome stability
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Identity

PubMed Central ID

  • PMC2845269

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/emboj.2009.413

PubMed ID

  • 20094029
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Additional Document Info

start page

  • 1136

end page

  • 1148

volume

  • 29

issue

  • 6

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