A defined role for multiple Fanconi anemia gene products in DNA-damage-associated ubiquitination.
Fanconi anemia (FA) is an inherited blood disorder that causes bone marrow failure and high predisposition to cancers. The FA pathway guards the cell's genome stability by orchestrating the repair of interstrand cross-linking during the S phase of the cell cycle, preventing the chromosomal instability that is a key event in bone marrow failure syndrome. Central to the FA pathway is loss of monoubiquitinated forms of the Fanconi proteins FANCI and FANCD2, a process that is normally mediated by a "core complex" of seven other Fanconi proteins. Each protein, when mutated, can cause FA. The FA core-complex-catalyzed reaction is critical for signaling DNA cross-link damage such as that induced by chemotherapies. Here, we present a perspective on the current understanding of FANCI and FANCD2 monoubiquitination-mediated DNA repair. Our recent biochemical reconstitution of the monoubiquitination (and deubiquitination) reactions creates a paradigm for understanding FA. Further biochemical analysis will create new opportunities to address the leukemic phenotype of FA patients.
Genome Stability Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Health, University of Melbourne, Fitzroy, Victoria, Australia.
Winnie
W
Tan
Genome Stability Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Health, University of Melbourne, Fitzroy, Victoria, Australia. Electronic address: adeans@svi.edu.au.
Andrew J
AJ
Deans
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D011485:Protein Binding; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D054875:Ubiquitination
D051856:Fanconi Anemia Complementation Group Proteins