Crosstalk between MSH2–MSH3 and polβ promotes trinucleotide repeat expansion during base excision repair

Authors

Yanhao Lai, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Helen Budworth, Lawrence Berkeley National Laboratory
Jill M. Beaver, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Nelson L.S. Chan, Lawrence Berkeley National Laboratory
Zunzhen Zhang, Sichuan UniversityFollow
Cynthia T. McMurray, Lawrence Berkeley National Laboratory
Yuan Liu, Biomolecular Sciences Institute and Department of Chemistry and Biochemistry, Florida International University, Miami, FloridaFollow

Date of this Version

8-22-2016

Document Type

Article

Rights

by

Abstract

Studies in knockout mice provide evidence that MSH2–MSH3 and the BER machinery promote trinucleotide repeat (TNR) expansion, yet how these two different repair pathways cause the mutation is unknown. Here we report the first molecular crosstalk mechanism, in which MSH2–MSH3 is used as a component of the BER machinery to cause expansion. On its own, pol β fails to copy TNRs during DNA synthesis, and bypasses them on the template strand to cause deletion. Remarkably, MSH2–MSH3 not only stimulates pol β to copy through the repeats but also enhances formation of the flap precursor for expansion. Our results provide direct evidence that MMR and BER, operating together, form a novel hybrid pathway that changes the outcome of TNR instability from deletion to expansion during the removal of oxidized bases. We propose that cells implement crosstalk strategies and share machinery when a canonical pathway is ineffective in removing a difficult lesion.

DOI

10.1038/ncomms12465

Identifier

FIDC001615

Comments

Originally Published in Nature Communications.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Lai, Y. et al. Crosstalk between MSH2–MSH3 and pol b promotes trinucleotide repeat expansion during base excision repair. Nat. Commun. 7:12465 doi: 10.1038/ncomms12465 (2016).