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Lethality in PARP-1/Ku80 double mutant mice reveals physiological synergy during early embryogenesis

2003; Elsevier BV; Volume: 2; Issue: 2 Linguagem: Inglês

10.1016/s1568-7864(02)00199-4

1568-7864

Melinda Henrie, Akihiro Kurimasa, Sandeep Burma, Josiane Ménissier‐de Murcia, Gilbert de Murcia, Gloria C. Li, David J. Chen,

Cell death mechanisms and regulation

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.