Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair.
Fanconi anemia (FA) is a developmental and cancer-predisposition syndrome caused by mutations in genes controlling DNA interstrand crosslink repair. Several FA proteins form a ubiquitin ligase that controls monoubiquitination of the FANCD2 protein in an ATR-dependent manner. Here we describe the FA protein FANCI, identified as an ATM/ATR kinase substrate required for resistance to mitomycin C. FANCI shares sequence similarity with FANCD2, likely evolving from a common ancestral gene. The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. Like FANCD2, FANCI is monoubiquitinated and unexpectedly, ubiquitination of each protein is important for the maintenance of ubiquitin on the other, indicating the existence of a dual ubiquitin-locking mechanism required for ID complex function. Mutation in FANCI is responsible for loss of a functional FA pathway in a patient with Fanconi anemia complementation group I.
Smogorzewska
Agata
A
Department of Genetics, Howard Hughes Medical Institute, Center for Genetics and Genomics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Matsuoka
Shuhei
S
Vinciguerra
Patrizia
P
McDonald
E Robert
ER
Hurov
Kristen E
KE
Luo
Ji
J
Ballif
Bryan A
BA
Gygi
Steven P
SP
Hofmann
Kay
K
D'Andrea
Alan D
AD
Elledge
Stephen J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000737:chemistry / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D016196:S Phase; D047270:Strongylocentrotus purpuratus; D025801:Ubiquitin / Q000378:metabolism*
C519921:FANCI protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D025801:Ubiquitin; D008239:Lysine