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.
Highlights
Histones H3 and H4 are methylated on several amino acid residues, and this methylation can proceed up to the triple level at individual amino acids, usually lysines or less frequently arginines
JMJD-1.1 is required for resistance to interstrand DNA crosslinks and double-strand DNA breaks in C. elegans
JMJD-1.1 and JMJD-1.2 proteins are very similar in amino acid sequences to human PHF8, which is a histone demethylase associated with X-linked mental retardation
Summary
Histones H3 and H4 are methylated on several amino acid residues, and this methylation can proceed up to the triple level at individual amino acids, usually lysines or less frequently arginines. Histone methylation patterns differ greatly between active and inactive genes, suggesting that histone methylation has a great impact on chromatin structure [1]. A well-known example is the histone H3 Lys tri-methylation and Lys hypomethylation in heterochromatin [2]. C. elegans Histone Demethylase in DNA Repair. DNA damage signaling as well as gene expression, is influenced by histone methylation, as in the case of 53BP1 binding to chromatin containing methylated H3K79 or H4K20 [3,4]. The methylation of the tumor suppressor p53 promotes its association with 53BP1 leading to transcriptional activation and apoptosis [6]
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