XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility.

Abstract

Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of ~26 months and a nearly identical maximal life expectancy of ~37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated-weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity-HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure.

• Authors: Daniel R McNeill, Ping-Chang Lin, Marshall G Miller, Paul J Pistell, Nadja C de Souza-Pinto, Kenneth W Fishbein, Richard G Spencer, Yie Liu, Christina Pettan-Brewer, Warren C Ladiges, David M Wilson 3rd
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 39 Issue 18 Pg. 7992-8004 (Oct 2011) ISSN: 1362-4962 [Electronic] England
• PMID: 21737425 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Alkylating Agents
• DNA-Binding Proteins
• Mutagens
• X-ray Repair Cross Complementing Protein 1
• Xrcc1 protein, mouse

Topics

• Aging (genetics)
• Alkylating Agents (toxicity)
• Animals
• Behavior, Animal
• Body Weight
• Bone Marrow Cells (drug effects)
• Brain (anatomy & histology, metabolism)
• Cell Survival (drug effects)
• Chemical and Drug Induced Liver Injury (pathology)
• DNA-Binding Proteins (genetics)
• Disease Susceptibility
• Female
• Genomic Instability
• Haploinsufficiency
• Male
• Mice
• Mice, Inbred C57BL
• Mutagens (toxicity)
• X-ray Repair Cross Complementing Protein 1