Dynamic human MutSα–MutLα complexes compact mismatched DNA

Public Deposited
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • Bradford K.C.
    • College of Arts and Sciences, Department of Chemistry
  • Wilkins H.
    • College of Arts and Sciences, Department of Chemistry
  • Hao P.
    • Other Affiliation: North Carolina State University
  • Li Z.M.
    • College of Arts and Sciences, Department of Physics and Astronomy
  • Wang B.
    • College of Arts and Sciences, Department of Chemistry
  • Burke D.
    • College of Arts and Sciences, Department of Physics and Astronomy
  • Wu D.
    • College of Arts and Sciences, Department of Chemistry
  • Smith A.E.
    • College of Arts and Sciences, Department of Chemistry
  • Spaller L.
    • College of Arts and Sciences, Department of Chemistry
  • Du C.
    • Other Affiliation: National Institutes of Health
  • Gauer J.W.
    • College of Arts and Sciences, Department of Chemistry
  • Chan E.
    • Other Affiliation: North Carolina State University
  • Hsieh P.
    • Other Affiliation: National Institutes of Health
  • Weninger K.R.
    • Other Affiliation: North Carolina State University
  • Erie D.A.
    • College of Arts and Sciences, Department of Chemistry
Abstract
  • DNA mismatch repair (MMR) corrects errors that occur during DNA replication. In humans, mutations in the proteins MutSα and MutLα that initiate MMR cause Lynch syndrome, the most common hereditary cancer. MutSα surveilles the DNA, and upon recognition of a replication error it undergoes adenosine triphosphate-dependent conformational changes and recruits MutLα. Subsequently, proliferating cell nuclear antigen (PCNA) activates MutLα to nick the error-containing strand to allow excision and resynthesis. The structure–function properties of these obligate MutSα–MutLα complexes remain mostly unexplored in higher eukaryotes, and models are predominately based on studies of prokaryotic proteins. Here, we utilize atomic force microscopy (AFM) coupled with other methods to reveal time- and concentration-dependent stoichiometries and conformations of assembling human MutSα–MutLα–DNA complexes. We find that they assemble into multimeric complexes comprising three to eight proteins around a mismatch on DNA. On the timescale of a few minutes, these complexes rearrange, folding and compacting the DNA. These observations contrast with dominant models of MMR initiation that envision diffusive MutS–MutL complexes that move away from the mismatch. Our results suggest MutSα localizes MutLα near the mismatch and promotes DNA configurations that could enhance MMR efficiency by facilitating MutLα nicking the DNA at multiple sites around the mismatch. In addition, such complexes may also protect the mismatch region from nucleosome reassembly until repair occurs, and they could potentially remodel adjacent nucleosomes.
Date of publication
Keyword
DOI
Identifier
Related resource URL
Resource type
  • Article
Journal title
  • 117
Journal issue
  • Proceedings of the National Academy of Sciences of the United States of America
Page start
  • 16302
Page end
  • 16312
Language
  • English
Funder
  • National Institutes of Health, NIH
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases, DIR, NIAID
  • National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK, (ZIADK052029)
  • National Institute of General Medical Sciences, NIGMS, (R01 GM079480, R01 GM109832, R01 GM132263, R35GM127151)
ISSN
  • 0027-8424
Publisher
  • National Academy of Sciences

Relations

Parents:

This work has no parents.

Items

Thumbnail Title Date Uploaded Visibility Actions
file details bradford-et-al-2020-dynamic-human-mutsa-mutla-complexes-compact-mismatched-dna.pdf 2024-01-23 Public Download
file details AFM data for Dynamic MutS-MuL complexes compact mismatched DNA 2020-06-04 Public