RRC ID 76106
Author Zhang X, Tian S, Beese-Sims SE, Chen J, Shin N, Colaiácovo MP, Kim HM.
Title Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.
Journal PLoS Genet
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.
Volume 17(7)
Pages e1009715
Published 2021-7-1
DOI 10.1371/journal.pgen.1009715
PII PGENETICS-D-21-00389
PMID 34329293
PMC PMC8357103
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans Caenorhabditis elegans Proteins Cell Nucleus / metabolism DNA Damage / genetics DNA Repair / genetics* DNA Repair / physiology Germ Cells / metabolism Histone Demethylases / metabolism* Histone Demethylases / physiology Histones / genetics Methylation Protein Processing, Post-Translational / genetics Ubiquitination
Resource
C.elegans tm2176 tm2181