期刊
NUCLEIC ACIDS RESEARCH
卷 40, 期 13, 页码 5965-5974出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks287
关键词
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资金
- TJ Park Science Fellowship
- National Research Foundation of Korea [20100017477, 2009-0086964]
- Agency for Science, Technology, and Research (A*STAR) of Singapore
- CHUNG Moon Soul Center of KAIST
- National Research Foundation of Korea [2009-0086964] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Phosphorylation of the histone variant H2AX forms gamma-H2AX that marks DNA double-strand break (DSB). Here, we generated the sequencing-based maps of H2AX and gamma-H2AX positioning in resting and proliferating cells before and after ionizing irradiation. Genome-wide locations of possible endogenous and exogenous DSBs were identified based on gamma-H2AX distribution in dividing cancer cells without irradiation and that in resting cells upon irradiation, respectively. gamma-H2AX-enriched regions of endogenous origin in replicating cells included sub-telomeres and active transcription start sites, apparently reflecting replication- and transcription-mediated stress during rapid cell division. Surprisingly, H2AX itself, prior to phosphorylation, was specifically located at these endogenous hotspots. This phenomenon was only observed in dividing cancer cells but not in resting cells. Endogenous H2AX was concentrated on the transcription start site of actively transcribed genes but was irrelevant to pausing of RNA polymerase II (pol II), which precisely coincided with gamma-H2AX of endogenous origin. gamma-H2AX enrichment upon irradiation also coincided with actively transcribed regions, but unlike endogenous gamma-H2AX, it extended into the gene body and was not specifically concentrated on the pausing site of pol II. Sub-telomeres were less responsive to external DNA damage than to endogenous stress. Our findings provide insight into DNA repair programs of cancer and may have implications for cancer therapy.
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