Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.

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 poor...

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Autores principales:	Xiaojuan Zhang, Sisi Tian, Sara E Beese-Sims, Jingjie Chen, Nara Shin, Monica P Colaiácovo, Hyun-Min Kim
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/2881f9edb3744b8f8faa11a7833c1199
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spelling	oai:doaj.org-article:2881f9edb3744b8f8faa11a7833c11992021-12-02T20:02:53ZHistone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.1553-73901553-740410.1371/journal.pgen.1009715https://doaj.org/article/2881f9edb3744b8f8faa11a7833c11992021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009715https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Histone 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.Xiaojuan ZhangSisi TianSara E Beese-SimsJingjie ChenNara ShinMonica P ColaiácovoHyun-Min KimPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009715 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Xiaojuan Zhang Sisi Tian Sara E Beese-Sims Jingjie Chen Nara Shin Monica P Colaiácovo Hyun-Min Kim Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.
description	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.
format	article
author	Xiaojuan Zhang Sisi Tian Sara E Beese-Sims Jingjie Chen Nara Shin Monica P Colaiácovo Hyun-Min Kim
author_facet	Xiaojuan Zhang Sisi Tian Sara E Beese-Sims Jingjie Chen Nara Shin Monica P Colaiácovo Hyun-Min Kim
author_sort	Xiaojuan Zhang
title	Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.
title_short	Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.
title_full	Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.
title_fullStr	Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.
title_full_unstemmed	Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.
title_sort	histone demethylase amx-1 is necessary for proper sensitivity to interstrand crosslink dna damage.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/2881f9edb3744b8f8faa11a7833c1199
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Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage.

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