Functional interplay between Parp-1 and SirT1 in genome integrity and chromatin-based processes.
Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD(+)-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development. We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone modifications associated with constitutive heterochromatin integrity.
El Ramy
Rosy
R
IREBS-FRE3211, ESBS, Bld S. Brant, BP10413, 67412, Illkirch, France.
Magroun
Najat
N
Messadecq
Nadia
N
Gauthier
Laurent R
LR
Boussin
François D
FD
Kolthur-Seetharam
Ullas
U
Schreiber
Valérie
V
McBurney
Michael W
MW
Sassone-Corsi
Paolo
P
Dantzer
Françoise
F
D000818:Animals; D002466:Cell Nucleolus / Q000648:ultrastructure; D049109:Cell Proliferation; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism / Q000502:physiology*; D004249:DNA Damage; D016678:Genome; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D006657:Histones; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins