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Nucleic Acids Res. 2012 Feb;40(4):1485-98. doi: 10.1093/nar/gkr868. Epub 2011 Oct 22.

FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA.

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1
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.

Abstract

We have previously reported that DT40 cells deficient in the Y-family polymerase REV1 are defective in replicating G-quadruplex DNA. In vivo this leads to uncoupling of DNA synthesis from redeposition of histones displaced ahead of the replication fork, which in turn leads to loss of transcriptional repression due to failure to recycle pre-existing repressive histone post-translational modifications. Here we report that a similar process can also affect transcriptionally active genes, leading to their deactivation. We use this finding to develop an assay based on loss of expression of a cell surface marker to monitor epigenetic instability at the level of single cells. This assay allows us to demonstrate G4 DNA motif-associated epigenetic instability in mutants of three helicases previously implicated in the unwinding of G-quadruplex structures, FANCJ, WRN and BLM. Transcriptional profiling of DT40 mutants reveals that FANCJ coordinates two independent mechanisms to maintain epigenetic stability near G4 DNA motifs that are dependent on either REV1 or on the WRN and BLM helicases, suggesting a model in which efficient in vivo replication of G-quadruplexes often requires the established 5'-3'-helicase activity of FANCJ acting in concert with either a specialized polymerase or helicase operating in the opposite polarity.

PMID:
22021381
PMCID:
PMC3287192
DOI:
10.1093/nar/gkr868
[Indexed for MEDLINE]
Free PMC Article
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