RRC ID 53492
Author Lee C, Hong S, Lee MH, Koo HS.
Title A PHF8 homolog in C. elegans promotes DNA repair via homologous recombination.
Journal PLoS One
Abstract PHF8 is a JmjC domain-containing histone demethylase, defects in which are associated with X-linked mental retardation. In this study, we examined the roles of two PHF8 homologs, JMJD-1.1 and JMJD-1.2, in the model organism C. elegans in response to DNA damage. A deletion mutation in either of the genes led to hypersensitivity to interstrand DNA crosslinks (ICLs), while only mutation of jmjd-1.1 resulted in hypersensitivity to double-strand DNA breaks (DSBs). In response to ICLs, JMJD-1.1 did not affect the focus formation of FCD-2, a homolog of FANCD2, a key protein in the Fanconi anemia pathway. However, the dynamic behavior of RPA-1 and RAD-51 was affected by the mutation: the accumulations of both proteins at ICLs appeared normal, but their subsequent disappearance was retarded, suggesting that later steps of homologous recombination were defective. Similar changes in the dynamic behavior of RPA-1 and RAD-51 were seen in response to DSBs, supporting a role of JMJD-1.1 in homologous recombination. Such a role was also supported by our finding that the hypersensitivity of jmjd-1.1 worms to ICLs was rescued by knockdown of lig-4, a homolog of Ligase 4 active in nonhomologous end-joining. The hypersensitivity of jmjd-1.1 worms to ICLs was increased by rad-54 knockdown, suggesting that JMJD-1.1 acts in parallel with RAD-54 in modulating chromatin structure. Indeed, the level of histone H3 Lys9 tri-methylation, a marker of heterochromatin, was higher in jmjd-1.1 cells than in wild-type cells. We conclude that the histone demethylase JMJD-1.1 influences homologous recombination either by relaxing heterochromatin structure or by indirectly regulating the expression of multiple genes affecting DNA repair.
Volume 10(4)
Pages e0123865
Published 2015-1-1
DOI 10.1371/journal.pone.0123865
PII PONE-D-14-47473
PMID 25853498
PMC PMC4390335
MeSH Animals Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism DNA Breaks, Double-Stranded* DNA Repair* Disease Models, Animal Fanconi Anemia Complementation Group D2 Protein / genetics Fanconi Anemia Complementation Group D2 Protein / metabolism Gene Expression Regulation Heterochromatin / chemistry Heterochromatin / metabolism Histone Demethylases / genetics* Histone Demethylases / metabolism Histones / genetics Histones / metabolism Homologous Recombination* Humans Isoenzymes / genetics Isoenzymes / metabolism Ligases / genetics Ligases / metabolism Mental Retardation, X-Linked / genetics Mental Retardation, X-Linked / metabolism Mental Retardation, X-Linked / pathology Rad51 Recombinase / genetics Rad51 Recombinase / metabolism Replication Protein A / genetics Replication Protein A / metabolism Sequence Homology, Amino Acid Signal Transduction Transcription Factors / genetics* Transcription Factors / metabolism
IF 2.74
Times Cited 7