The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response.
Cells from Fanconi anemia (FA) patients are extremely sensitive to DNA interstrand crosslinking (ICL) agents, but the molecular basis of the hypersensitivity remains to be explored. FANCM (FA complementation group M), and its binding partner, FAAP24, anchor the multisubunit FA core complex to chromatin after DNA damage and may contribute to ICL-specific cellular response. Here we show that the FANCM/FAAP24 complex is specifically required for the recruitment of replication protein A (RPA) to ICL-stalled replication forks. ICL-induced RPA foci formation requires the DNA-binding activity of FAAP24 but not the DNA translocase activity of FANCM. Furthermore, FANCM/FAAP24-dependent RPA foci formation is required for efficient ATR-mediated checkpoint activation in response to ICL. Therefore, we propose that FANCM/FAAP24 plays a role in ICL-induced checkpoint activation through regulating RPA recruiment at ICL-stalled replication forks.
Huang
Min
M
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Kim
Jung Min
JM
Shiotani
Bunsyo
B
Yang
Kailin
K
Zou
Lee
L
D'Andrea
Alan D
AD
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D002843:Chromatin; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C518296:FAAP24 protein, human; D051856:Fanconi Anemia Complementation Group Proteins; D046912:Multiprotein Complexes; D051716:Replication Protein A; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C518295:FANCM protein, human; D004265:DNA Helicases