FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA
Open Access
- 22 October 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 40 (4), 1485-1498
- https://doi.org/10.1093/nar/gkr868
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.Keywords
This publication has 69 references indexed in Scilit:
- Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndromeThe EMBO Journal, 2011
- Epigenetic Instability due to Defective Replication of Structured DNAMolecular Cell, 2010
- The Werner's Syndrome protein collaborates with REV1 to promote replication fork progression on damaged DNADNA Repair, 2010
- Making copies of chromatin: the challenge of nucleosomal organization and epigenetic informationTrends in Cell Biology, 2009
- A model for transmission of the H3K27me3 epigenetic markNature, 2008
- High-Resolution Profiling of Histone Methylations in the Human GenomeCell, 2007
- Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genomeNature Genetics, 2007
- Multiple Mechanisms Control Chromosome Integrity after Replication Fork Uncoupling and Restart at Irreparable UV LesionsMolecular Cell, 2006
- The DNA helicase BRIP1 is defective in Fanconi anemia complementation group JNature Genetics, 2005
- RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMONature, 2002