Fanconi anemia protein FANCD2 promotes immunoglobulin gene conversion and DNA repair through a mechanism related to homologous recombination.
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.
Yamamoto
Kazuhiko
K
Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
Hirano
Seiki
S
Ishiai
Masamichi
M
Morishima
Kenichi
K
Kitao
Hiroyuki
H
Namikoshi
Keiko
K
Kimura
Masayo
M
Matsushita
Nobuko
N
Arakawa
Hiroshi
H
Buerstedde
Jean-Marie
JM
Komatsu
Kenshi
K
Thompson
Larry H
LH
Takata
Minoru
M
D000818:Animals; D030161:Avian Proteins; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002645:Chickens; D002869:Chromosome Aberrations; D002945:Cisplatin / Q000494:pharmacology; D003001:Cloning, Molecular; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein; D016195:G2 Phase; D007075:Immunoglobulin M / Q000737:chemistry; D007136:Immunoglobulins / Q000378:metabolism*; D008938:Mitosis; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D016196:S Phase; D012854:Sister Chromatid Exchange; D013997:Time Factors; D014162:Transfection; D014466:Ultraviolet Rays; D014965:X-Rays
D030161:Avian Proteins; D004268:DNA-Binding Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein; D007075:Immunoglobulin M; D007136:Immunoglobulins; D009687:Nuclear Proteins; C495150:RAD51 protein, Gallus gallus; D051135:Rad51 Recombinase; D002945:Cisplatin