title: 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.
authors.affiliation: DNA Damage Response Laboratory, Cancer Research UK, Clare Hall, EN6 3LD South Mimms, UK.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Collis
authors.forename: Alberto
authors.initials: A
authors.lastname: Ciccia
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Deans
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Horejsí
authors.forename: Julie S
authors.initials: JS
authors.lastname: Martin
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Maslen
authors.forename: J Mark
authors.initials: JM
authors.lastname: Skehel
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: Stephen C
authors.initials: SC
authors.lastname: West
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins; D016678:Genome; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C518296:FAAP24 protein, human; D051856:Fanconi Anemia Complementation Group Proteins; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C518295:FANCM protein, human; D004265:DNA Helicases