Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction.
Fanconi anemia is a cancer-prone inherited bone marrow failure and cancer susceptibility syndrome with at least 13 complementation groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN). Our laboratory has previously described several regulatory phosphorylation events for core complex member proteins FANCG and FANCA by phosphorylation. In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage-inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2. A phosphomimetic mutation at S331 restores all of these phenotypes to wild-type. In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1, the S-phase checkpoint kinase implicated in the Fanconi anemia DNA repair pathway.
Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia, USA.
Gang
G
Zhi
James B
JB
Wilson
Xiaoyong
X
Chen
Diane S
DS
Krause
Yuxuan
Y
Xiao
Nigel J
NJ
Jones
Gary M
GM
Kupfer
D000595:Amino Acid Sequence; D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism*; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000502:physiology; D005199:Fanconi Anemia / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine; D015398:Signal Transduction / Q000502:physiology*
D024682:BRCA2 Protein; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D012694:Serine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1