Research article summary (published 11 Jul 2009):

The concerted action of Msh2 and UNG stimulates somatic hypermutation at A . T base pairs.

Full Abstract

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 approximately 200 nucleotides long and that polymerase eta makes approximately 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.

Author information

Author/s: Frieder, Darina (D); Larijani, Mani (M); Collins, Cathy (C); Shulman, Marc (M); Martin, Alberto (A);

Affiliation: Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Molecular and cellular biology (Mol Cell Biol), published in United States. (Language: eng)

Reference: 2009-Sep; vol 29 (issue 18) : pp 5148-57

Dates: Created 2009/08/27; Completed 2009/09/15; Revised 2009/09/15;

PMID: 19596785, status: MEDLINE (last retrieved date: 9/16/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Adenine - metabolism Animals Base Pairing - genetics Cytidine Deaminase - metabolism DNA Mismatch Repair - drug effects Enzyme Inhibitors - pharmacology Immunoglobulins - genetics Mice

Mice Models, Biological MutS Homolog 2 Protein - metabolism Mutagenesis - drug effects Mutation - genetics Somatic Hypermutation, Immunoglobulin - drug effects; genetics Thymine - metabolism Uracil-DNA Glycosidase - antagonists & inhibitors; metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Enzyme Inhibitors (0) ; Immunoglobulins (0) ; Thymine (65-71-4) ; Adenine (73-24-5) ; Uracil-DNA Glycosidase (EC 3.2.2.-) ; AICDA (activation-induced cytidine deaminase) (EC 3.5.4.-) ; Cytidine Deaminase (EC 3.5.4.5) ; Msh2 protein, mouse (EC 3.6.1.3) ; MutS Homolog 2 Protein (EC 3.6.1.3)

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