Skip to main content
Journal cover image

Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.

Publication ,  Journal Article
Kadyrova, LY; Gujar, V; Burdett, V; Modrich, PL; Kadyrov, FA
Published in: Proc Natl Acad Sci U S A
February 18, 2020

MutL proteins are ubiquitous and play important roles in DNA metabolism. MutLγ (MLH1-MLH3 heterodimer) is a poorly understood member of the eukaryotic family of MutL proteins that has been implicated in triplet repeat expansion, but its action in this deleterious process has remained unknown. In humans, triplet repeat expansion is the molecular basis for ∼40 neurological disorders. In addition to MutLγ, triplet repeat expansion involves the mismatch recognition factor MutSβ (MSH2-MSH3 heterodimer). We show here that human MutLγ is an endonuclease that nicks DNA. Strikingly, incision of covalently closed, relaxed loop-containing DNA by human MutLγ is promoted by MutSβ and targeted to the strand opposite the loop. The resulting strand break licenses downstream events that lead to a DNA expansion event in human cell extracts. Our data imply that the mammalian MutLγ is a unique endonuclease that can initiate triplet repeat DNA expansions.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 18, 2020

Volume

117

Issue

7

Start / End Page

3535 / 3542

Location

United States

Related Subject Headings

  • Trinucleotide Repeat Expansion
  • MutL Proteins
  • MutL Protein Homolog 1
  • Humans
  • Endonucleases
  • Dimerization
  • DNA Mismatch Repair
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kadyrova, L. Y., Gujar, V., Burdett, V., Modrich, P. L., & Kadyrov, F. A. (2020). Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion. Proc Natl Acad Sci U S A, 117(7), 3535–3542. https://doi.org/10.1073/pnas.1914718117
Kadyrova, Lyudmila Y., Vaibhavi Gujar, Vickers Burdett, Paul L. Modrich, and Farid A. Kadyrov. “Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.Proc Natl Acad Sci U S A 117, no. 7 (February 18, 2020): 3535–42. https://doi.org/10.1073/pnas.1914718117.
Kadyrova LY, Gujar V, Burdett V, Modrich PL, Kadyrov FA. Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion. Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3535–42.
Kadyrova, Lyudmila Y., et al. “Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.Proc Natl Acad Sci U S A, vol. 117, no. 7, Feb. 2020, pp. 3535–42. Pubmed, doi:10.1073/pnas.1914718117.
Kadyrova LY, Gujar V, Burdett V, Modrich PL, Kadyrov FA. Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion. Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3535–3542.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 18, 2020

Volume

117

Issue

7

Start / End Page

3535 / 3542

Location

United States

Related Subject Headings

  • Trinucleotide Repeat Expansion
  • MutL Proteins
  • MutL Protein Homolog 1
  • Humans
  • Endonucleases
  • Dimerization
  • DNA Mismatch Repair