Volume 31, No 5, May 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 5, May 2021: 542-553   |  Open Access

ORIGINAL ARTICLES

Mispair-bound human MutS–MutL complex triggers DNA incisions and activates mismatch repair

Janice Ortega¹ , Grace Sanghee Lee^2,3 , Liya Gu¹ , Wei Yang³ , Guo-Min Li^1,2,*

¹Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
²Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA
³Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
⁴Present address: Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA These authors contributed equally: Janice Ortega, Grace Sanghee Lee
These authors contributed equally: Janice Ortega, Grace Sanghee Lee Correspondence: Guo-Min Li(guo-min.li@utsouthwestern.edu)

DNA mismatch repair (MMR) relies on MutS and MutL ATPases for mismatch recognition and strand-specific nuclease recruitment to remove mispaired bases in daughter strands. However, whether the MutS–MutL complex coordinates MMR by ATP-dependent sliding on DNA or protein–protein interactions between the mismatch and strand discrimination signal is ambiguous. Using functional MMR assays and systems preventing proteins from sliding, we show that sliding of human MutSα is required not for MMR initiation, but for final mismatch removal. MutSα recruits MutLα to form a mismatch-bound complex, which initiates MMR by nicking the daughter strand 5′ to the mismatch. Exonuclease 1 (Exo1) is then recruited to the nick and conducts 5′ → 3′ excision. ATP-dependent MutSα dissociation from the mismatch is necessary for Exo1 to remove the mispaired base when the excision reaches the mismatch. Therefore, our study has resolved a long-standing puzzle, and provided new insights into the mechanism of MMR initiation and mispair removal.

https://doi.org/10.1038/s41422-021-00468-y

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