dna repair 5 (2006) 1392–1397
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/dnarepair
Developmental cell death in the liver and newborn
lethality of Ku86 deficient mice suppressed by
antioxidant N-acetyl-cysteine
Ramune Reliene
a,b,c
, Marry E.P. Goad
d
, Robert H. Schiestl
a,b,c,∗
a
Department of Pathology, Geffen School of Medicine, UCLA,
650 Charles E. Young Drive South, Los Angeles, CA 90024, United States
b
Department of Environmental Health, School of Public Health, UCLA,
650 Charles E. Young Drive South, Los Angeles, CA 90024, United States
c
Department of Radiation Oncology, Geffen School of Medicine, UCLA,
650 Charles E. Young Drive South, Los Angeles, CA 90024, United States
d
Peptimmune, Inc., 64 Sidney St., Cambridge, MA 02139, United States
article info
Article history:
Received 26 May 2006
Accepted 20 June 2006
Published on line 17 August 2006
Keywords:
Ku86
Mouse
Fetal liver
Apoptosis
Necrosis
N-Acetyl-cysteine
Oxidative stress
abstract
Repair of DNA double-strand breaks (DSBs) is essential for genome integrity and cell sur-
vival. Ku86 is involved in the repair of DNA DSBs by non-homologous end joining (NHEJ).
Mice deficient in Ku86 showgrowth retardation, dwarfism, premature aging, and immunode-
ficiency. In this study, we observed severely compromised survival of Ku86
−/−
mice, such that
most Ku86
−/−
mice died within the first postnatal weeks and only 1.5% of the expected 25%
from heterozygous crosses survived for 1 month. Since post-mortem analysis was not possi-
ble due to parental cannibalism, histopathological examination was performed on Ku86
−/−
fetuses to assess possible causes of newborn death. Eighty percent and 75% of Ku86
−/−
fetuses exhibited apoptosis and necrosis in the liver, while only 20% and 10% of Ku86
+/+
littermates had apoptosis and necrosis, respectively. In addition, the severity of liver dam-
age was significantly higher in Ku86
−/−
fetuses. Developmental liver damage may have led to
postnatal lethality because the fetal liver with pre-existing injury may not be able to undergo
transformation from a lymphohematopoietic to an indispensable metabolic organ. Free rad-
icals can cause chromosomal breaks and lead to cell death. We postulated that endogenous
oxidative stress might be involved in the resulting liver damage and animal lethality in
Ku86
−/−
mice deficient in DNA DSB repair. This hypothesis was tested by treating Ku86
−/−
mice with the well known free radical scavenger, thiol antioxidant N-acetyl-cysteine (NAC),
during embryonic development. We found that a significantly higher percentage, 7.7% of
NAC treated Ku86
−/−
offspring versus 1.5% untreated Ku86
−/−
mice were alive at 1 month of
age. In addition, the incidence of liver necrosis decreased by 21% and the severity of necrosis
significantly reduced. Thus, Ku86 deficiency results in severe developmental liver damage
and newborn lethality associated with oxidative stress.
© 2006 Elsevier B.V. All rights reserved.
∗
Corresponding author. Tel.: +1 310 267 2087; fax: +1 310 267 2578.
E-mail address: rschiestl@mednet.ucla.edu (R.H. Schiestl).
1568-7864/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.dnarep.2006.06.007