FANCL replaces BRCA1 as the likely ubiquitin ligase responsible for FANCD2 monoubiquitination.
Monoubiquitination of FANCD2 is a key step in the DNA damage response pathway involving Fanconi anemia proteins and the breast cancer susceptibility gene products, BRCA1 and BRCA2. One critical unresolved issue is the identity of the ubiquitin ligase responsible for this reaction. Two proteins, BRCA1 and FANCL(PHF9), have been suggested to be this ligase. Here we found that FANCL, but not BRCA1, evolutionarily co-exists with FANCD2 in several species. Moreover, the proportion of FANCD2 in chromatin and nuclear matrix is drastically reduced in a cell line mutated in FANCL, but not in that mutated in BRCA1. This defective distribution of FANCD2 in the FANCL-mutant cell line is likely due to its defective monoubiquitination, because the monoubiquitinated FANCD2 preferentially associates with chromatin and nuclear matrix, whereas non-ubiquitinated FANCD2 largely resides in the soluble fraction. Our data support the notion that FANCL, but not BRCA1, is the likely ligase for FANCD2 monoubiquitination.
Meetei
Amom R
AR
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Yan
Zhijiang
Z
Wang
Weidong
W
D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D017360:Arabidopsis / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D004330:Drosophila / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein; D052240:Fanconi Anemia Complementation Group L Protein; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016415:Sequence Alignment
D019313:BRCA1 Protein; D024682:BRCA2 Protein; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein; D008025:Ligases