期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 13, 页码 8768-8776出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806103200
关键词
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资金
- W.W. Smith Charitable Trust
- American Cancer Society Institutional Grant [IRG 78-002-29]
- Abramson Family Cancer Research Institute
Genome integrity is maintained during DNA replication by coordination of various replisome-regulated processes. Although it is known that Timeless (Tim) is a replisome component that participates in replication checkpoint responses to genotoxic stress, its importance for genome maintenance during normal DNA synthesis has not been reported. Here we demonstrate that Tim reduction leads to genomic instability during unperturbed DNA replication, culminating in increased chromatid breaks and translocations (triradials, quadriradials, and fusions). Tim deficiency led to increased H2AX phosphorylation and Rad51 and Rad52 foci formation selectively during DNA synthesis and caused a 3-4-fold increase in sister chromatid exchange. The sister chromatid exchange events stimulated by Tim reduction were largely mediated via a Brca2/Rad51-dependent mechanism and were additively increased by deletion of the Blm helicase. Therefore, Tim deficiency leads to an increased reliance on homologous recombination for proper continuation of DNA synthesis. Together, these results indicate a pivotal role for Tim in maintaining genome stability throughout normal DNA replication.
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