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

Yanhao Lai, Helen Budworth, Jill M. Beaver, Nelson L. S. Chan, Zunzhen Zhang, Cynthia T. McMurray () and Yuan Liu ()
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Yanhao Lai: Florida International University
Helen Budworth: Lawrence Berkeley National Laboratory
Jill M. Beaver: Biochemistry Ph.D. Program, Florida International University
Nelson L. S. Chan: Lawrence Berkeley National Laboratory
Zunzhen Zhang: Sichuan University West China School of Public Health
Cynthia T. McMurray: Lawrence Berkeley National Laboratory
Yuan Liu: Florida International University

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12465

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