title: Crosstalk between MSH2-MSH3 and polβ promotes trinucleotide repeat expansion during base excision repair.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Miami, Florida 33199, USA.
authors.forename: Yanhao
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, 33R249, Berkeley, California 94720, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Budworth
authors.affiliation: Biochemistry Ph.D. Program, Florida International University, 11200 SW 8th Street, Miami, Florida 33199, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Beaver
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, 33R249, Berkeley, California 94720, USA.
authors.forename: Nelson L S
authors.initials: NL
authors.lastname: Chan
authors.affiliation: Department of Occupational and Environmental Health, Sichuan University West China School of Public Health, 16#, Section 3, Renmin Nan Lu, Chengdu, Sichuan 610041, China.
authors.forename: Zunzhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, 33R249, Berkeley, California 94720, USA.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Miami, Florida 33199, USA.|Biochemistry Ph.D. Program, Florida International University, 11200 SW 8th Street, Miami, Florida 33199, USA.|Biomolecular Sciences Institute, School of Integrated Sciences and Humanity, Florida International University, 11200 SW 8th Street, Miami, Florida 33199, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism*; D004260:DNA Repair; D033862:Iron-Binding Proteins / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism; D008954:Models, Biological; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D000074081:MutS Homolog 3 Protein / Q000378:metabolism*; D011485:Protein Binding; D013379:Substrate Specificity; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D000096923:Frataxin
chemical_list: D004247:DNA; D019951:DNA Polymerase beta; D033862:Iron-Binding Proteins; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D000096923:Frataxin