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

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

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)151-158
Number of pages8
JournalDNA repair
Volume2
Issue number2
DOIs
StatePublished - Feb 3 2003

Keywords

  • Base excision repair
  • Embryonic lethality
  • Homologous repair
  • Ku80
  • PARP-1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Henrie, M. S., Kurimasa, A., Burma, S., Ménissier-de Murcia, J., De Murcia, G., Li, G. C., & Chen, D. J. (2003). Lethality in PARP-1/Ku80 double mutant mice reveals physiological synergy during early embryogenesis. DNA repair, 2(2), 151-158. https://doi.org/10.1016/S1568-7864(02)00199-4