Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota

Nature ◽  
2002 ◽  
Vol 419 (6910) ◽  
pp. 944-947 ◽  
Author(s):  
Ahmad Faili ◽  
Said Aoufouchi ◽  
Eric Flatter ◽  
Quentin Guéranger ◽  
Claude-Agnès Reynaud ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Somatic Hypermutation ◽  
Immunoglobulin Genes ◽  
Dna Polymerase Iota

scholarly journals Reevaluation of the role of DNA polymerase θ in somatic hypermutation of immunoglobulin genes

DNA Repair ◽  
2008 ◽  
Vol 7 (9) ◽  
pp. 1603-1608 ◽  
Author(s):  
Stella A. Martomo ◽  
Huseyin Saribasak ◽  
Masayuki Yokoi ◽  
Fumio Hanaoka ◽  
Patricia J. Gearhart
Keyword(s):  
Dna Polymerase ◽  
Somatic Hypermutation ◽  
Immunoglobulin Genes

scholarly journals DNA Polymerase and dRP-lyase activities of polymorphic variants of human Pol ι

2021 ◽  
Vol 478 (7) ◽  
pp. 1399-1412
Author(s):  
Evgeniy S. Shilkin ◽  
Anastasia S. Gromova ◽  
Margarita P. Smal ◽  
Alena V. Makarova
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
Polymerase Activity ◽  
Altered Expression ◽  
Dna Polymerase Iota ◽  
Nucleotide Incorporation ◽  
Lyase Activity ◽  
Polymorphic Variants ◽  
Y Family

Y-family DNA polymerase iota (Pol ι) is involved in DNA damage response and tolerance. Mutations and altered expression level of POLI gene are linked to a higher incidence of cancer. We biochemically characterized five active site polymorphic variants of human Pol ι: R71G (rs3218778), P118L (rs554252419), I236M (rs3218784), E251K (rs3218783) and P365R (rs200852409). We analyzed fidelity of nucleotide incorporation on undamaged DNA, efficiency and accuracy of DNA damage bypass, as well as 5′-deoxyribophosphate lyase (dRP-lyase) activity. The I236M and P118L variants were indistinguishable from the wild-type Pol ι in activity. The E251K and P365R substitutions altered the spectrum of nucleotide incorporation opposite several undamaged DNA bases. The P365R variant also reduced the dRP-lyase activity and possessed the decreased TLS activity opposite 8-oxo-G. The R71G mutation dramatically affected the catalytic activities of Pol ι. The reduced DNA polymerase activity of the R71G variant correlated with an enhanced fidelity of nucleotide incorporation on undamaged DNA, altered lesion-bypass activity and reduced dRP-lyase activity. Therefore, this amino acid substitution likely alters Pol ι functions in vivo.

scholarly journals Inaccurate DNA Synthesis in Cell Extracts of Yeast Producing Active Human DNA Polymerase Iota

PLoS ONE ◽  
2011 ◽  
Vol 6 (1) ◽  
pp. e16612 ◽  
Author(s):  
Alena V. Makarova ◽  
Corinn Grabow ◽  
Leonid V. Gening ◽  
Vyacheslav Z. Tarantul ◽  
Tahir H. Tahirov ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Dna Polymerase ◽  
Dna Polymerase Iota ◽  
Cell Extracts ◽  
Human Dna

DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes

10.1038/88740 ◽  
2001 ◽  
Vol 2 (6) ◽  
pp. 537-541 ◽  
Author(s):  
Xianmin Zeng ◽  
David B. Winter ◽  
Cynthia Kasmer ◽  
Kenneth H. Kraemer ◽  
Alan R. Lehmann ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Somatic Hypermutation ◽  
Immunoglobulin Variable Genes ◽  
Variable Genes

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

2005 ◽  
Vol 201 (4) ◽  
pp. 637-645 ◽  
Author(s):  
Teresa M. Wilson ◽  
Alexandra Vaisman ◽  
Stella A. Martomo ◽  
Patsa Sullivan ◽  
Li Lan ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Base Excision Repair ◽  
Somatic Hypermutation ◽  
Excision Repair ◽  
Cytidine Deaminase ◽  
Abasic Site ◽  
Cell Extracts ◽  
Activation Induced Cytidine Deaminase ◽  
Base Excision

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.

Sign in / Sign up

Export Citation Format

Share Document