Genome-wide reorganization of histone H2AX toward particular fragile sites on cell activation

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gamma H2AX formation by phosphorylation of the histone variant H2AX is the key process in the repair of DNA lesions including those arising at fragile sites under replication stress. Here we demonstrate that H2AX is dynamically reorganized to preoccupy gamma H2AX hotspots on increased replication stress by activated cell proliferation and that H2AX is enriched in aphidicolin-induced replisome stalling sites in cycling cells. Interestingly, H2AX enrichment was particularly found in genomic regions that replicate in early S phase. High transcription activity, a hallmark of early replicating fragile sites, was a determinant of H2AX localization. Subtelomeric H2AX enrichment was also attributable to early replication and high gene density. In contrast, late replicating and infrequently transcribed regions, including common fragile sites and heterochromatin, lacked H2AX enrichment. In particular, heterochromatin was inaccessible to H2AX incorporation, maybe partly explaining the cause of mutation accumulation in cancer heterochromatin. Meanwhile, H2AX in actively dividing cells was intimately colocalized with INO80. INO80 silencing reduced H2AX levels, particularly at the INO80-enriched sites. Our findings suggest that active DNA replication is accompanied with the specific localization of H2AX and INO80 for efficient damage repair or replication-fork stabilization in actively transcribed regions.
Publisher
OXFORD UNIV PRESS
Issue Date
2014-01
Language
English
Article Type
Article
Citation

NUCLEIC ACIDS RESEARCH, v.42, no.2, pp.1016 - 1025

ISSN
0305-1048
DOI
10.1093/nar/gkt951
URI
http://hdl.handle.net/10203/190199
Appears in Collection
MSE-Journal Papers(저널논문)BiS-Journal Papers(저널논문)
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