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

Yanhao Lai,Nelson L S Chan,Zunzhen Zhang,Yuan Liu,Jill M Beaver,Helen Budworth,Cynthia T Mcmurray

doi:10.1038/ncomms12465

Yanhao Lai, Nelson L S Chan + Show 5 more

Open Access

https://doi.org/10.1038/ncomms12465

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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.

Highlights

Studies in knockout mice provide evidence that MutS homologue 2 (MSH2)–MutS homologue 3 (MSH3) and the base excision repair (BER) machinery promote trinucleotide repeat (TNR) expansion, yet how these two different repair pathways cause the mutation is unknown
An abasic site forms as a BER intermediate after the damaged base is removed by a DNA glycosylase, and the 50-end is processed by apyrimidinic endonuclease 1 (APE1) forming a gap that is filled by a DNA polymerase, often polymerase b
Since MSH2–MSH3, OGG1, NEIL1 and pol b have been implicated in causing expansions in mice, we asked whether there are interactions between the mismatch repair (MMR) and BER machinery

Summary

Introduction

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. 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. Human cell line experiments agree with the fact that MSH3 is the causative agent, and MSH6 is less important in this process[26] These unexpected results provided genetic evidence that MSH2–MSH3 causes, rather than corrects, the expansion mutation. The results from diverse model organisms imply that other DNA repair pathways can promote TNR expansion, the preponderance of evidence indicates that the MMR system remains arguably the most important. It remains highly controversial how MSH2–MSH3 causes expansion

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