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

Citation:

Simon Yuan Wang*, Mao Hui*, Hiroki Shibuya*, Satoru Uzawa, Zach Klapholz O'Brown, Sage Wesenberg, Nara Shin, Takamune Saito, Jinmin Gao, Barbara J. Meyer, Monica P Colaiacovo, and Eric Lieberman Greer. 7/8/2019. “The demethylase NMAD-1 regulates DNA replication and repair in the C. elegans germline.” PLOS Genetics. Publisher's Version
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The demethylase NMAD-1 regulates DNA replication and repair in the C. elegans germline

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-1mutants 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.
Last updated on 10/18/2020