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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Caenorhabditis elegans / genetics*
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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DNA Breaks, Double-Stranded*
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DNA Repair*
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Disease Models, Animal
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Fanconi Anemia Complementation Group D2 Protein / genetics
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Fanconi Anemia Complementation Group D2 Protein / metabolism
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Gene Expression Regulation
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Heterochromatin / chemistry
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Heterochromatin / metabolism
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Histone Demethylases / genetics*
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Histone Demethylases / metabolism
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Histones / genetics
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Histones / metabolism
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Homologous Recombination*
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Humans
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Ligases / genetics
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Ligases / metabolism
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Mental Retardation, X-Linked / genetics
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Mental Retardation, X-Linked / metabolism
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Mental Retardation, X-Linked / pathology
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Rad51 Recombinase / genetics
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Rad51 Recombinase / metabolism
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Replication Protein A / genetics
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Replication Protein A / metabolism
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Sequence Homology, Amino Acid
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Signal Transduction
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Transcription Factors / genetics*
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Transcription Factors / metabolism
Substances
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Caenorhabditis elegans Proteins
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FANCD2 protein, human
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Fanconi Anemia Complementation Group D2 Protein
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Heterochromatin
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Histones
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Isoenzymes
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RPA1 protein, human
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Replication Protein A
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Transcription Factors
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Histone Demethylases
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PHF8 protein, human
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Rad51 Recombinase
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rad-51 protein, C elegans
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Ligases
Grants and funding
This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0023645) to HSK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.