FANCM regulates DNA chain elongation and is stabilized by S-phase checkpoint signalling.
FANCM binds and remodels replication fork structures in vitro. We report that in vivo, FANCM controls DNA chain elongation in an ATPase-dependent manner. In the presence of replication inhibitors that do not damage DNA, FANCM counteracts fork movement, possibly by remodelling fork structures. Conversely, through damaged DNA, FANCM promotes replication and recovers stalled forks. Hence, the impact of FANCM on fork progression depends on the underlying hindrance. We further report that signalling through the checkpoint effector kinase Chk1 prevents FANCM from degradation by the proteasome after exposure to DNA damage. FANCM also acts in a feedback loop to stabilize Chk1. We propose that FANCM is a ringmaster in the response to replication stress by physically altering replication fork structures and by providing a tight link to S-phase checkpoint signalling.
Luke-Glaser
Sarah
S
Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges s/Lausanne, Switzerland.
Luke
Brian
B
Grossi
Simona
S
Constantinou
Angelos
A
D000251:Adenosine Triphosphatases / Q000378:metabolism; D001483:Base Sequence; D000071877:Checkpoint Kinase 1; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication / Q000502:physiology*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016196:S Phase; D015398:Signal Transduction
C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D034741:RNA, Small Interfering; D004247:DNA; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C518295:FANCM protein, human; D004265:DNA Helicases