FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex.

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 Cell

journal_title

Molecular cell

authors

Collis SJ,Ciccia A,Deans AJ,Horejsí Z,Martin JS,Maslen SL,Skehel JM,Elledge SJ,West SC,Boulton SJ

doi

10.1016/j.molcel.2008.10.014

subject

Has Abstract

pub_date

2008-11-07 00:00:00

pages

313-24

issue

3

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(08)00729-6

journal_volume

32

pub_type

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