Abstract
Histone methylation is dynamically regulated to shape the epigenome and adjust central nuclear processes including transcription, cell cycle control and DNA repair. Lysine-specific histone demethylase 2 (LSD2) has been implicated in multiple types of human cancers. However, its functions remain poorly understood. This study investigated the histone demethylase LSD2 homolog AMX-1 in C. elegans and uncovered a potential link between H3K4me2 modulation and DNA interstrand crosslink (ICL) repair. AMX-1 is a histone demethylase and mainly localizes to embryonic cells, the mitotic gut and sheath cells. Lack of AMX-1 expression resulted in embryonic lethality, a decreased brood size and disorganized premeiotic tip germline nuclei. Expression of AMX-1 and of the histone H3K4 demethylase SPR-5 is reciprocally up-regulated upon lack of each other and the mutants show increased H3K4me2 levels in the germline, indicating that AMX-1 and SPR-5 regulate H3K4me2 demethylation. Loss of AMX-1 function activates the CHK-1 kinase acting downstream of ATR and leads to the accumulation of RAD-51 foci and increased DNA damage-dependent apoptosis in the germline. AMX-1 is required for the proper expression of mismatch repair component MutL/MLH-1 and sensitivity against ICLs. Interestingly, formation of ICLs lead to ubiquitination-dependent subcellular relocalization of AMX-1. Taken together, our data suggest that AMX-1 functions in ICL repair in the germline.
Highlights
A nucleosome consists of a H2A, H2B, H3 and H4 histone octamer wrapped around by DNA and further condensed into chromatin [1]
Epigenetic failures in DNA damage repair have long been implicated in multiple types of human cancers, including colorectal and stomach cancer
H3K4me2 is modulated by the Fanconi anemia pathway connecting the regulation of histone methylation level to DNA damage repair [13]
Summary
A nucleosome consists of a H2A, H2B, H3 and H4 histone octamer wrapped around by DNA and further condensed into chromatin [1]. Histones undergo post-translational modifications at various sites along their tails, such as methylation, acetylation, and phosphorylation [2]. These modifications affect chromatin structure and help orchestrate events such as transcription, DNA damage repair, and meiotic crossover recombination [1]. LSD1, the first histone demethylase identified, reverses mono- or di-methylation of H3K4 in promoter regions in human cells [6]. Other studies discovered that this histone demethylase is essential for DNA double-strand break (DSB) repair and p53-dependent germ cell apoptosis in the C. elegans germline [11], linking H3K4me modulation to DSB repair. H3K4me is modulated by the Fanconi anemia pathway connecting the regulation of histone methylation level to DNA damage repair [13]
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