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 |