NSMF promotes the replication stress-induced DNA damage response for genome maintenance. Issue 10 (8th May 2021)

• Record Type: Journal Article
• Authors: Ju, Min Kyung; Shin, Kyeong Jin; Lee, Joo Rak; Khim, Keon Woo; A. Lee, Eun; Ra, Jae Sun; Kim, Byung-Gyu; Jo, Han-seul; Yoon, Jong Hyuk; Kim, Tae Moon; Myung, Kyungjae; Choi, Jang Hyun; Kim, Hongtae; Chae, Young Chan
• Is Part Of: Nucleic acids research. Volume 49:Issue 10(2021)
• Page Start: 5605
• Page End: 5622
• Publication Date: 2021-05-08
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkab311
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Proper activation of DNA repair pathways in response to DNA replication stress is critical for maintaining genomic integrity. Due to the complex nature of the replication fork (RF), problems at the RF require multiple proteins, some of which remain unidentified, for resolution. In this study, we identified the N-methyl-D-aspartate receptor synaptonuclear signaling and neuronal migration factor (NSMF) as a key replication stress response factor that is important for ataxia telangiectasia and Rad3-related protein (ATR) activation. NSMF localizes rapidly to stalled RFs and acts as a scaffold to modulate replication protein A (RPA) complex formation with cell division cycle 5-like (CDC5L) and ATR/ATR-interacting protein (ATRIP). Depletion of NSMF compromised phosphorylation and ubiquitination of RPA2 and the ATR signaling cascade, resulting in genomic instability at RFs under DNA replication stress. Consistently, NSMF knockout mice exhibited increased genomic instability and hypersensitivity to genotoxic stress. NSMF deficiency in human and mouse cells also caused increased chromosomal instability. Collectively, these findings demonstrate that NSMF regulates the ATR pathway and the replication stress response network for genome maintenance and cell survival.