Abstract:
: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 cell-cycle checkpoint responses. Moreover, we find that the DNA translocase activity of FANCM, which is dispensable for FA pathway activation, is required for its role in ATR/Chk1 signaling. Our data suggest that DNA damage recognition and remodeling activities of FANCM and FAAP24 cooperate with ATR/Chk1 to promote efficient activation of DNA damage checkpoints.
journal_name
Mol Celljournal_title
Molecular cellauthors
Collis SJ,Ciccia A,Deans AJ,Horejsí Z,Martin JS,Maslen SL,Skehel JM,Elledge SJ,West SC,Boulton SJdoi
10.1016/j.molcel.2008.10.014subject
Has Abstractpub_date
2008-11-07 00:00:00pages
313-24issue
3eissn
1097-2765issn
1097-4164pii
S1097-2765(08)00729-6journal_volume
32pub_type
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