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Nucleic Acids Res., 2023 May 4;gkad30 | https://doi.org/10.1093/nar/gkad308 MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1

Jung-Min Oh^1,2†*, Yujin Kang ^3†, Jumi Park ³, Yubin Sung ¹, Dayoung Kim ⁴, Yuri Seo ¹, Eun A Lee ¹, Jae Sun Ra¹, Enkhzul Amarsanaa^1,3, Young-Un Park ¹, Seon Young Lee ¹, Jung Me Hwang¹, Hongtae Kim ^1,3, Orlando Schärer ^1,3, Seung Woo Cho ^1,4, Changwook Lee ³, Kei-Ichi Takata ^1,3, Ja Yil Lee ^1,3*, Kyungjae Myung^1,4*

¹Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea.
²Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
³Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan44919, Republic of Korea.
⁴Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan44919, Republic of Korea.

*Correspondence: Jung-Min Oh, Ja Yil Lee, Kyungjae Myung
†The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors
Present address: Yuri Seo, Chungnam National University, Daejeon, Republic of Korea.
Present address: Young-Un Park, CasCure Therapeutics, Ulsan, Republic of Korea

Abstract

DNA double-strand break (DSB) repair via homologous recombination is initiated by end resection. The extent of DNA end resection determines the choice of the DSB repair pathway. Nucleases for end resection have been extensively studied. However, it is still unclear how the potential DNA structures generated by the initial short resection by MRE11-RAD50-NBS1 are recognized and recruit proteins, such as EXO1, to DSB sites to facilitate long-range resection. We found that the MSH2-MSH3 mismatch repair complex is recruited to DSB sites through interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 facilitates the recruitment of EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 also inhibits access of POLθ, which promotes polymerase theta-mediated end-joining (TMEJ). Collectively, we present a direct role of MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing the DSB repair pathway by favoring homologous recombination over TMEJ.

논문정보

형식Research article
게재일2023년 05월 (BRIC 등록일 2023-05-15)
연구진국내 연구진
분야 생명과학 > 분자생물학

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