Base excision repair proteins couple activation-induced cytidine deaminase and endonuclease G during replication stress-induced MLL destabilization

Leukemia ◽  
2017 ◽  
Vol 32 (1) ◽  
pp. 159-167 ◽  
Author(s):  
B Gole ◽  
E Mian ◽  
M Rall ◽  
L Wiesmüller
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Cytidine Deaminase ◽  
Replication Stress ◽  
Endonuclease G ◽  
Activation Induced Cytidine Deaminase ◽  
Base Excision

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.

scholarly journals MBD4 Facilitates Immunoglobulin Class Switch Recombination

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Fernando Grigera ◽  
Robert Wuerffel ◽  
Amy L. Kenter
Keyword(s):  
Excision Repair ◽  
Cytidine Deaminase ◽  
Ectopic Expression ◽  
Class Switch Recombination ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Class Switch ◽  
Activation Induced Cytidine Deaminase ◽  
Base Excision

ABSTRACT Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double-strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation-induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme methyl-CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when Mbd4 exons 6 to 8 are deleted in a switching B cell line, DSB formation is severely reduced and CSR frequency is impaired. Impaired CSR can be rescued by ectopic expression of Mbd4. Mbd4 deficiency yields a deficit in DNA end processing similar to that found in MutS homologue 2 (Msh2)- and Mlh1-deficient B cells. We demonstrate that microhomology-rich S-S junctions are enriched in cells in which Mbd4 is deleted. Our studies suggest that Mbd4 is a component of MMR-directed DNA end processing.

scholarly journals Programmable C:G to G:C genome editing with CRISPR-Cas9-directed base excision repair proteins

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Liwei Chen ◽  
Jung Eun Park ◽  
Peter Paa ◽  
Priscilla D. Rajakumar ◽  
Hong-Ting Prekop ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Excision Repair ◽  
Cytidine Deaminase ◽  
Genetic Diseases ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Base Excision ◽  
Nucleotide Resolution

AbstractMany genetic diseases are caused by single-nucleotide polymorphisms. Base editors can correct these mutations at single-nucleotide resolution, but until recently, only allowed for transition edits, addressing four out of twelve possible DNA base substitutions. Here, we develop a class of C:G to G:C Base Editors to create single-base genomic transversions in human cells. Our C:G to G:C Base Editors consist of a nickase-Cas9 fused to a cytidine deaminase and base excision repair proteins. Characterization of >30 base editor candidates reveal that they predominantly perform C:G to G:C editing (up to 90% purity), with rAPOBEC-nCas9-rXRCC1 being the most efficient (mean 15.4% and up to 37% without selection). C:G to G:C Base Editors target cytidine in WCW, ACC or GCT sequence contexts and within a precise three-nucleotide window of the target protospacer. We further target genes linked to dyslipidemia, hypertrophic cardiomyopathy, and deafness, showing the therapeutic potential of these base editors in interrogating and correcting human genetic diseases.

Modulation of Base Excision Repair Alters Cellular Sensitivity to UVA1 but not to UVB¶

2002 ◽  
Vol 75 (5) ◽  
pp. 507 ◽  
Author(s):  
Katherine J. Kim ◽  
Indraneel Chakrabarty ◽  
Guang-Zhi Li ◽  
Sabine Grösch ◽  
Bernd Kaina ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Cellular Sensitivity ◽  
Base Excision

Defective Base Excision Repair Associated with NTHL1

2019 ◽  
Vol 68 ◽  
Author(s):  
Richarda de Voer ◽  
Paul W Doetsch ◽  
Roland Kuiper ◽  
Barbara Rivera
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Base Excision

A new DNA breaks repair pathway involving PARP3 and base excision repair proteins

2018 ◽  
Vol 482 (1) ◽  
pp. 96-100
Author(s):  
E. Belousova ◽  
◽  
M. Kutuzov ◽  
P. Ivankina ◽  
A. Ishchenko ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Pathway ◽  
Dna Breaks ◽  
Base Excision
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