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

Autor: Hyun-Min Kim, Sara E. Beese-Sims, Xiaojuan Zhang, Sisi Tian, Jingjie Chen, Nara Shin, Monica P. Colaiácovo
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Nematoda
DNA Repair
Apoptosis
QH426-470
Biochemistry
Germline
Histones
Animals
Genetically Modified
RNA interference
0302 clinical medicine
Histone methylation
Medicine and Health Sciences
Genetics (clinical)
Histone Demethylases
Cell Death
biology
Eukaryota
Animal Models
Cell biology
Nucleic acids
Histone
Experimental Organism Systems
Genetic interference
Cell Processes
030220 oncology & carcinogenesis
Epigenetics
DNA mismatch repair
Anatomy
Genital Anatomy
Research Article
DNA repair
DNA damage
Research and Analysis Methods
Methylation
03 medical and health sciences
Model Organisms
DNA-binding proteins
Genetics
Animals
Gonads
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Cell Nucleus
Biology and life sciences
Reproductive System
Organisms
Ubiquitination
Proteins
DNA
Cell Biology
Epigenome
Invertebrates
Germ Cells
030104 developmental biology
Animal Studies
Caenorhabditis
biology.protein
RNA
Demethylase
Gene expression
Zoology
Protein Processing
Post-Translational
Zdroj: PLoS Genetics, Vol 17, Iss 7, p e1009715 (2021)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Author summary Epigenetic failures in DNA damage repair have long been implicated in multiple types of human cancers, including colorectal and stomach cancer. Several studies reported histone demethylases’ roles in DNA damage repair; however, the mechanisms by which histone demethylases contribute to DNA damage repair are not very clear. Here, we describe a mammalian LSD2 homolog AMX-1 in C. elegans and uncover a potential link between H3K4me2 modulation and DNA interstrand crosslink repair. AMX-1 mainly localizes to embryonic cells, the mitotic gut and sheath cells. AMX-1 regulates H3K4me2 demethylation and is necessary for sensitivity against interstrand crosslink damage.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje