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Molecular and Cellular Biology, September 2009, p. 5148-5157, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00647-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Concerted Action of Msh2 and UNG Stimulates Somatic Hypermutation at A · T Base Pairs{triangledown} ,{dagger}

Darina Frieder, Mani Larijani, Cathy Collins, Marc Shulman, and Alberto Martin*

Department of Immunology, University of Toronto, Medical Sciences Building, Toronto M5S 1A8, Canada

Received 19 May 2009/ Returned for modification 22 June 2009/ Accepted 6 July 2009

Mismatch repair plays an essential role in reducing the cellular mutation load. Paradoxically, proteins in this pathway produce A·T mutations during the somatic hypermutation of immunoglobulin genes. Although recent evidence implicates the translesional DNA polymerase {eta} in producing these mutations, it is unknown how this or other translesional polymerases are recruited to immunoglobulin genes, since these enzymes are not normally utilized in conventional mismatch repair. In this report, we demonstrate that A·T mutations were closely associated with transversion mutations at a deoxycytidine. Furthermore, deficiency in uracil-N-glycolase (UNG) or mismatch repair reduced this association. These data reveal a previously unknown interaction between the base excision and mismatch repair pathways and indicate that an abasic site generated by UNG within the mismatch repair tract recruits an error-prone polymerase, which then introduces A·T mutations. Our analysis further indicates that repair tracts typically are ~200 nucleotides long and that polymerase {eta} makes ~1 error per 300 T nucleotides. The concerted action of Msh2 and UNG in stimulating A·T mutations also may have implications for mutagenesis at sites of spontaneous cytidine deamination.

* Corresponding author. Mailing address: Department of Immunology, University of Toronto, Medical Sciences Bldg. 5265, Toronto M5S 1A8, Canada. Phone: (416) 978-4235. Fax: (416) 978-1938. E-mail: alberto.martin{at}utoronto.ca

{triangledown} Published ahead of print on 13 July 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2009, p. 5148-5157, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00647-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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