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Title: Lethality in PARP-1/Ku80 double mutant mice reveals physiologicalsynergy during early embryogenesis

Abstract

Ku is an abundant heterodimeric nuclear protein, consisting of 70-kDa 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.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director, Office of Science. Office of Biological andEnvironmental Research. Life Sciences Division
OSTI Identifier:
917337
Report Number(s):
LBNL-51541
R&D Project: 860G15; BnR: 400412000; TRN: US200816%%529
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
DNA Repair
Additional Journal Information:
Journal Volume: 2; Journal Issue: 3; Related Information: Journal Publication Date: 02/03/2003
Country of Publication:
United States
Language:
English
Subject:
59; APOPTOSIS; BIOLOGICAL PATHWAYS; DEATH; DNA; EXCISION REPAIR; IN VITRO; IN VIVO; MICE; MUTANTS; ONTOGENESIS; PROGENY; PROTEINS; REPAIR; STRAND BREAKS; SYNTHESIS; TARGETS

Citation Formats

Henrie, Melinda S., Kurimasa, Akihiro, Burma, Sandeep, Menissier-de Murcia, Josiane, de Murcia, Gilbert, Li, Gloria C., and Chen,David J. Lethality in PARP-1/Ku80 double mutant mice reveals physiologicalsynergy during early embryogenesis. United States: N. p., 2002. Web.
Henrie, Melinda S., Kurimasa, Akihiro, Burma, Sandeep, Menissier-de Murcia, Josiane, de Murcia, Gilbert, Li, Gloria C., & Chen,David J. Lethality in PARP-1/Ku80 double mutant mice reveals physiologicalsynergy during early embryogenesis. United States.
Henrie, Melinda S., Kurimasa, Akihiro, Burma, Sandeep, Menissier-de Murcia, Josiane, de Murcia, Gilbert, Li, Gloria C., and Chen,David J. Tue . "Lethality in PARP-1/Ku80 double mutant mice reveals physiologicalsynergy during early embryogenesis". United States. https://www.osti.gov/servlets/purl/917337.
@article{osti_917337,
title = {Lethality in PARP-1/Ku80 double mutant mice reveals physiologicalsynergy during early embryogenesis},
author = {Henrie, Melinda S. and Kurimasa, Akihiro and Burma, Sandeep and Menissier-de Murcia, Josiane and de Murcia, Gilbert and Li, Gloria C. and Chen,David J.},
abstractNote = {Ku is an abundant heterodimeric nuclear protein, consisting of 70-kDa 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.},
doi = {},
journal = {DNA Repair},
number = 3,
volume = 2,
place = {United States},
year = {2002},
month = {9}
}