FANCM and FAAP24 Function in ATR-Mediated Checkpoint Signaling Independently of the Fanconi Anemia Core Complex
Spencer J Collis, Alberto Ciccia, Andrew J Deans, Zuzana Horejsi, Julie S Martin, Sarah L Maslen, J Mark Skehel, Stephen J Elledge, Stephen C West, Simon J Boulton
Molecular Cell | CELL PRESS | Published : 2008
The Fanconi anemia (FA) pathway is implicated in DNA repair and cancer predisposition. Central to this pathway is the FA core complex, which is targeted to chromatin by FANCM and FAAP24 following replication stress. Here we show that FANCM and FAAP24 interact with the checkpoint protein HCLK2 independently of the FA core complex. In addition to defects in FA pathway activation, downregulation of FANCM or FAAP24 also compromises ATR/Chk1-mediated checkpoint signaling, leading to defective Chk1, p53, and FANCE phosphorylation; 53BP1 focus formation; and Cdc25A degradation. As a result, FANCM and FAAP24 deficiency results in increased endogenous DNA damage and a failure to efficiently invoke ce..View full abstract
We would like to thank the CRUK Cell Production Facility and Hideaki Matsui for technical assistance and Drs. Janet Cronshaw (CRUK LRI Institute, London), Alan D'Andrea (Harvard Medical School, Boston), and Ketan Patel (MRC LMB Institute, Cambridge) for kind gifts of reagents. S.J.E. is a Howard Hughes Medical Institute Investigator. This work was supported by grants from the National Institutes of Health (S.J.E.), Cancer Research UK (S.C.W. and S.J.B.), the Louis-Jeantet Foundation and EU DNA Repair Consortium (S.C.W.), and the Fanconi Anemia Research Fund (S.J.C. and S.J.B.).