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MSH2–MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes

By Teresa M. Wilson, Alexandra Vaisman, Stella A. Martomo, Patsa Sullivan, Li Lan, Fumio Hanaoka, Akira Yasui, Roger Woodgate and Patricia J. Gearhart

Abstract

Activation-induced cytidine deaminase deaminates cytosine to uracil (dU) in DNA, which leads to mutations at C:G basepairs in immunoglobulin genes during somatic hypermutation. The mechanism that generates mutations at A:T basepairs, however, remains unclear. It appears to require the MSH2–MSH6 mismatch repair heterodimer and DNA polymerase (pol) η, as mutations of A:T are decreased in mice and humans lacking these proteins. Here, we demonstrate that these proteins interact physically and functionally. First, we show that MSH2–MSH6 binds to a U:G mismatch but not to other DNA intermediates produced during base excision repair of dUs, including an abasic site and a deoxyribose phosphate group. Second, MSH2 binds to pol η in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2–MSH6 stimulates the catalytic activity of pol η in vitro. These observations suggest that the interaction between MSH2–MSH6 and DNA pol η stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs

Topics: Article
Publisher: The Rockefeller University Press
OAI identifier: oai:pubmedcentral.nih.gov:2213055
Provided by: PubMed Central
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    1. (2003). 129-derived strains of mice are deficient in DNA polymerase and have normal immunoglobulin hypermutation.
    2. (2004). 645 ARTICLE complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells.
    3. (2004). A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination.
    4. Absence of DNA polymerase reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions.
    5. Activation-induced cytidine deaminase (AID) causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2).
    6. (2003). Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase.
    7. (2002). Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas.
    8. (2002). AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts.
    9. (2003). AID mediates hypermutation by deaminating single stranded DNA.
    10. (2002). AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification.
    11. (2004). Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1-mutant mice.
    12. Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2.
    13. (2002). Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase.
    14. (2000). Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.
    15. (2003). Constitutive expression of AID leads to tumorigenesis.
    16. (2002). Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase during copying of a mouse immunoglobulin light chain transgene.
    17. (2001). Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase .
    18. (2004). Deletion of the nucleotide excision repair gene Ercc1 reduces immunoglobulin class switching and alters mutations near switch recombination junctions.
    19. (1999). Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications.
    20. (1999). Dissociation of mismatch recognition and ATPase activity by hMSH2-hMSH3.
    21. (2002). DNA polymerase deficiency does not affect somatic hypermutation in mice.
    22. (2001). DNA polymerase is an A-T mutator in somatic hypermutation of immunoglobulin variable genes.
    23. (2004). DNA polymerase is involved in hypermutation occurring during immunoglobulin class switch recombination.
    24. (2002). DNA polymerases and are dispensable for Ig gene hypermutation.
    25. (1985). DNA precursor pools and ribonucleotide reductase activity: distribution between the nucleus and cytoplasm of mammalian cells.
    26. (2004). DNA substrate length and surrounding sequence affect the activation induced deaminase activity at cytidine.
    27. (2001). Domain structure, localization, and function of DNA polymerase , defective in xeroderma pigmentosum variant cells. Genes Dev.
    28. (1991). Efficient selection for high-expression transfectants with a novel eukaryotic vector.
    29. (2004). Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification.
    30. (1995). Gel fidelity assay measuring nucleotide misinsertion, exonucleolytic proofreading, and lesion bypass efficiencies. Methods Enzymol.
    31. (1998). Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting.
    32. Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations. Nucleic Acids Res.
    33. (1998). Human exonuclease I interacts with the mismatch repair protein hMSH2. Cancer Res.
    34. (2003). Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination.
    35. (1999). Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein.
    36. Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice.
    37. (2002). Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice.
    38. (1998). Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein.
    39. (2003). Induction of somatic hypemutation is associated with modifications in immunoglobulin variable region chromatin.
    40. (2002). Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota.
    41. (2002). Involvement of DNA mismatch repair in folate deficiency-induced apoptosis.
    42. (2003). Localization of DNA polymerase and to the replication machinery is tightly co-ordinated in human cells.
    43. (2000). Mechanisms of accurate translesion synthesis by human DNA polymerase .
    44. (2000). Mice reconstituted with DNA polymerase -deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normally.
    45. (2004). Mismatch recognition and uracil-excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation.
    46. (1998). Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process.
    47. (2003). Msh2 ATPase activity is essential for somatic hypermutation at A-T basepairs and for efficient class switch recombination.
    48. (2000). Pol , a remarkably error-prone human DNA polymerase.
    49. (2004). Preferential cis-syn thymine dimer bypass by DNA polymerase occurs with biased fidelity.
    50. (2003). Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation.
    51. (2004). Recombinogenic phenotype of human activation-induced cytosine deaminase.
    52. (2003). Replication of damaged DNA.
    53. (2004). Replication protein A interacts with AID to promote deamination of somatic hypermutation targets.
    54. (2000). Replication protein A physically interacts with the Bloom’s syndrome protein and stimulates its helicase activity.
    55. (2000). Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern.
    56. (2001). Somatic mutation hotspots correlate with DNA polymerase error spectrum.
    57. (2001). Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination.
    58. (1997). The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch.
    59. (2002). The roots of antibody diversity.
    60. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand.
    61. (2003). Transcription-targeted DNA deamination by the AID antibody diversification enzyme.
    62. (2004). YB-1 promotes strand separation in vitro of duplex DNA containing either mispaired bases or cisplatin modifications, exhibits endonucleolytic activities and binds several DNA repair proteins. Nucleic Acids Res.

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