Journal
EMBO JOURNAL
Volume 29, Issue 6, Pages 1136-1148Publisher
WILEY
DOI: 10.1038/emboj.2009.413
Keywords
chromatin; DNA replication; genome stability; Schizosaccharomyces pombe; X-ray crystal structure
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Funding
- Canadian Institutes of Health Research (CIHR)
- Alberta Heritage Foundation for Medical Research (AHFMR)
- Skaggs Institute for Chemical Biology
- National Cancer Institute [CA117638, GM59447, CA77325]
- Integrated Diffraction Analysis Technologies (IDAT) under DOE [DE-AC02-05CH11231]
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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 (gamma H2A/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 gamma H2A 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. gamma H2A binding is critical for Brc1 function. The 1.45 angstrom resolution crystal structure of Brc1-gamma H2A 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 gamma H2A emerges as a critical chromatin-specific response to replication-associated DNA damage. The EMBO Journal (2010) 29, 1136-1148. doi: 10.1038/emboj.2009.413; Published online 21 January 2010
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