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The demethylase NMAD-1 regulates DNA replication and repair in the Caenorhabditis elegans germline.

Journal article
Authors Simon Yuan Wang
Hui Mao
Hiroki Shibuya
Satoru Uzawa
Zach Klapholz O'Brown
Sage Wesenberg
Nara Shin
Takamune T Saito
Jinmin Gao
Barbara J Meyer
Monica P Colaiácovo
Eric Lieberman Greer
Published in PLoS genetics
Volume 15
Issue 7
Pages e1008252
ISSN 1553-7404
Publication year 2019
Published at
Pages e1008252
Language en
Links dx.doi.org/10.1371/journal.pgen.100...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Biological Sciences, Genetics

Abstract

The biological roles of nucleic acid methylation, other than at the C5-position of cytosines in CpG dinucleotides, are still not well understood. Here, we report genetic evidence for a critical role for the putative DNA demethylase NMAD-1 in regulating meiosis in C. elegans. nmad-1 mutants have reduced fertility. They show defects in prophase I of meiosis, which leads to reduced embryo production and an increased incidence of males due to defective chromosomal segregation. In nmad-1 mutant worms, nuclear staging beginning at the leptotene and zygotene stages is disorganized, the cohesin complex is mislocalized at the diplotene and diakinesis stages, and chromosomes are improperly condensed, fused, or lost by the end of diakinesis. RNA sequencing of the nmad-1 germline revealed reduced induction of DNA replication and DNA damage response genes during meiosis, which was coupled with delayed DNA replication, impaired DNA repair and increased apoptosis of maturing oocytes. To begin to understand how NMAD-1 regulates DNA replication and repair, we used immunoprecipitation and mass spectrometry to identify NMAD-1 binding proteins. NMAD-1 binds to multiple proteins that regulate DNA repair and replication, including topoisomerase TOP-2 and co-localizes with TOP-2 on chromatin. Moreover, the majority of TOP-2 binding to chromatin depends on NMAD-1. These results suggest that NMAD-1 functions at DNA replication sites to regulate DNA replication and repair during meiosis.

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