Lethality in PARP-1/Ku80 double mutant mice reveals physiological synergy during early embryogenesis.
Ku is an abundant heterodimeric nuclear protein, consisting of 70- and 86-kDa tightly associated subunits that comprise the DNA binding component of DNA-dependent protein kinase. Poly(ADP-ribose) polymerase-1 (PARP-1) is a 113-kDa protein that catalyzes the synthesis of poly(ADP-ribose) on target proteins. Both Ku and PARP-1 recognize and bind to DNA ends. Ku functions in the non-homologous end joining (NHEJ) repair pathway whereas PARP-1 functions in the single strand break repair and base excision repair (BER) pathways. Recent studies have revealed that PARP-1 and Ku80 interact in vitro. To determine whether the association of PARP-1 and Ku80 has any physiological significance or synergistic function in vivo, mice lacking both PARP-1 and Ku80 were generated. The resulting offspring died during embryonic development displaying abnormalities around the gastrulation stage. In addition, PARP-1-/-/Ku80-/- cultured blastocysts had an increased level of apoptosis. These data suggest that the functions of both Ku80 and PARP-1 are essential for normal embryogenesis and that a loss of genomic integrity leading to cell death through apoptosis is likely the cause of the embryonic lethality observed in these mice.
Henrie
Melinda S
MS
Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA.
Kurimasa
Akihiro
A
Burma
Sandeep
S
Ménissier-de Murcia
Josiane
J
de Murcia
Gilbert
G
Li
Gloria C
GC
Chen
David J
DJ
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004265:DNA Helicases; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D005804:Genes, Lethal; D000072200:Ku Autoantigen; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D011065:Poly(ADP-ribose) Polymerases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen