Faculty Opinions recommendation of Fanconi anemia protein FANCD2 promotes immunoglobulin gene conversion and DNA repair through a mechanism related to homologous recombination.

2005 ◽  
Author(s):  
David Schatz
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Gene Conversion ◽  
Fanconi Anemia ◽  
Immunoglobulin Gene

scholarly journals Fanconi Anemia Protein FANCD2 Promotes Immunoglobulin Gene Conversion and DNA Repair through a Mechanism Related to Homologous Recombination

2005 ◽  
Vol 25 (1) ◽  
pp. 34-43 ◽  
Author(s):  
Kazuhiko Yamamoto ◽  
Seiki Hirano ◽  
Masamichi Ishiai ◽  
Kenichi Morishima ◽  
Hiroyuki Kitao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Gene Conversion ◽  
Fanconi Anemia ◽  
Strand Break ◽  
Immunoglobulin Gene ◽  
Dna Double Strand Break ◽  
Mutant Cells ◽  
Light Chain Locus

ABSTRACT Recent studies show overlap between Fanconi anemia (FA) proteins and those involved in DNA repair mediated by homologous recombination (HR). However, the mechanism by which FA proteins affect HR is unclear. FA proteins (FancA/C/E/F/G/L) form a multiprotein complex, which is responsible for DNA damage-induced FancD2 monoubiquitination, a key event for cellular resistance to DNA damage. Here, we show that FANCD2-disrupted DT40 chicken B-cell line is defective in HR-mediated DNA double-strand break (DSB) repair, as well as gene conversion at the immunoglobulin light-chain locus, an event also mediated by HR. Gene conversions occurring in mutant cells were associated with decreased nontemplated mutations. In contrast to these defects, we also found increased spontaneous sister chromatid exchange (SCE) and intact Rad51 foci formation after DNA damage. Thus, we propose that FancD2 promotes a subpathway of HR that normally mediates gene conversion by a mechanism that avoids crossing over and hence SCEs.

scholarly journals Role for RAD18 in Homologous Recombination in DT40 Cells

2006 ◽  
Vol 26 (21) ◽  
pp. 8032-8041 ◽  
Author(s):  
Dávid Szüts ◽  
Laura J. Simpson ◽  
Sarah Kabani ◽  
Mitsuyoshi Yamazoe ◽  
Julian E. Sale
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Gene Conversion ◽  
Early Stage ◽  
Current Evidence ◽  
Recombination Reaction ◽  
Immunoglobulin Gene ◽  
Postreplication Repair ◽  
Strand Breaks ◽  
Dt40 Cells

ABSTRACT RAD18 is an E3 ubiquitin ligase that catalyzes the monoubiquitination of PCNA, a modification central to DNA damage bypass and postreplication repair in both yeast and vertebrates. Although current evidence suggests that homologous recombination provides an essential backup in vertebrate rad18 mutants, we show that in chicken DT40 cells this is not the case and that RAD18 plays a role in the recombination reaction itself. Gene conversion tracts in the immunoglobulin locus of rad18 cells are shorter and are associated with an increased frequency of deletions and duplications. rad18 cells also exhibit reduced efficiency of gene conversion induced by targeted double-strand breaks in a reporter construct. Blocking an early stage of the recombination reaction by disruption of XRCC3 not only suppresses immunoglobulin gene conversion but also prevents the aberrant immunoglobulin gene rearrangements associated with RAD18 deficiency, reverses the elevated sister chromatid exchange of the rad18 mutant, and reduces its sensitivity to DNA damage. Together, these data suggest that homologous recombination is toxic in the absence of RAD18 and show that, in addition to its established role in postreplication repair, RAD18 is also required for the orderly completion of gene conversion.

scholarly journals The 9-1-1 DNA Clamp Is Required for Immunoglobulin Gene Conversion

2008 ◽  
Vol 28 (19) ◽  
pp. 6113-6122 ◽  
Author(s):  
Alihossein Saberi ◽  
Makoto Nakahara ◽  
Julian E. Sale ◽  
Koji Kikuchi ◽  
Hiroshi Arakawa ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Gene Conversion ◽  
Translesion Synthesis ◽  
Strand Break ◽  
Double Strand Break ◽  
Immunoglobulin Gene ◽  
Abasic Sites ◽  
Immunoglobulin Locus ◽  
Activation Induced Deaminase ◽  
Dt40 Cells

ABSTRACT Chicken DT40 cells deficient in the 9-1-1 checkpoint clamp exhibit hypersensitivity to a variety of DNA-damaging agents. Although recent work suggests that, in addition to its role in checkpoint activation, this complex may play a role in homologous recombination and translesion synthesis, the cause of this hypersensitivity has not been studied thoroughly. The immunoglobulin locus of DT40 cells allows monitoring of homologous recombination and translesion synthesis initiated by activation-induced deaminase (AID)-dependent abasic sites. We show that both the RAD9 −/− and RAD17 −/− mutants exhibit substantially reduced immunoglobulin gene conversion. However, the level of nontemplated immunoglobulin point mutation increased in these mutants, a finding that is reminiscent of the phenotype resulting from the loss of RAD51 paralogs or Brca2. This suggests that the 9-1-1 complex does not play a central role in translesion synthesis in this context. Despite reduced immunoglobulin gene conversion, the RAD9 −/− and RAD17 −/− cells do not exhibit a prominent defect in double-strand break-induced gene conversion or a sensitivity to camptothecin. This suggests that the roles of Rad9 and Rad17 may be confined to a subset of homologous recombination reactions initiated by replication-stalling lesions rather than those associated with double-strand break repair.

scholarly journals Fen-1 Facilitates Homologous Recombination by Removing Divergent Sequences at DNA Break Ends

2005 ◽  
Vol 25 (16) ◽  
pp. 6948-6955 ◽  
Author(s):  
Koji Kikuchi ◽  
Yoshihito Taniguchi ◽  
Atsushi Hatanaka ◽  
Eiichiro Sonoda ◽  
Helfrid Hochegger ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Sequence Divergence ◽  
Immunoglobulin Gene ◽  
Damage Site ◽  
Break Site ◽  
Dna Break ◽  
Dna Ends ◽  
Divergent Sequences

ABSTRACT Homologous recombination (HR) requires nuclease activities at multiple steps, but the contribution of individual nucleases to the processing of double-strand DNA ends at different stages of HR has not been clearly defined. We used chicken DT40 cells to investigate the role of flap endonuclease 1 (Fen-1) in HR. FEN-1-deficient cells exhibited a significant decrease in the efficiency of immunoglobulin gene conversion while being proficient in recombination between sister chromatids, suggesting that Fen-1 may play a role in HR between sequences of considerable divergence. To clarify whether sequence divergence at DNA ends is truly the reason for the observed HR defect in FEN-1 −/− cells we inserted a unique I-SceI restriction site in the genome and tested various donor and recipient HR substrates. We found that the efficiency of HR-mediated DNA repair was indeed greatly diminished when divergent sequences were present at the DNA break site. We conclude that Fen-1 eliminates heterologous sequences at DNA damage site and facilitates DNA repair by HR.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

scholarly journals ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

iScience ◽  
2021 ◽  
pp. 102534
Author(s):  
Shibin Xu ◽  
Xingxuan Wu ◽  
Peipei Wang ◽  
Sheng-Li Cao ◽  
Bin Peng ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination
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