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
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).
Rights Statement
In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/
This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
Comments
Originally Published in Nature Communications.