The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways.
Genomic stability requires a functional Fanconi anemia (FA) pathway composed of an upstream "core complex" (FA proteins A/B/C/E/F/G/L/M) that mediates monoubiquitination of the downstream targets FANCD2 and FANCI. Unique among FA core complex members, FANCM has processing activities toward replication-associated DNA structures, suggesting a vital role for FANCM during replication. Using Xenopus egg extracts, we analyzed the functions of FANCM in replication and the DNA damage response. xFANCM binds chromatin in a replication-dependent manner and is phosphorylated in response to DNA damage structures. Chromatin binding and DNA damage-induced phosphorylation of xFANCM are mediated in part by the downstream FA pathway protein FANCD2. Moreover, phosphorylation and chromatin recruitment of FANCM is regulated by two mayor players in the DNA damage response: the cell cycle checkpoint kinases ATR and ATM. Our results indicate that functions of FANCM are controlled by FA- and non-FA pathways in the DNA damage response.
Sobeck
Alexandra
A
Department of Biochemistry, Oregon Health and Science University, Portland, Oregon 97239, USA.
Stone
Stacie
S
Landais
Igor
I
de Graaf
Bendert
B
Hoatlin
Maureen E
ME
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin; D004249:DNA Damage / Q000502:physiology*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; C576898:Atr protein, Xenopus; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C544332:FANCM protein, Xenopus