Cargando…

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

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 heterozygo...

Descripción completa

Detalles Bibliográficos
Autores principales: McNeill, Daniel R., Lin, Ping-Chang, Miller, Marshall G., Pistell, Paul J., de Souza-Pinto, Nadja C., Fishbein, Kenneth W., Spencer, Richard G., Liu, Yie, Pettan-Brewer, Christina, Ladiges, Warren C., Wilson, David M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185405/
https://www.ncbi.nlm.nih.gov/pubmed/21737425
http://dx.doi.org/10.1093/nar/gkr280
_version_ 1782213206778839040
author McNeill, Daniel R.
Lin, Ping-Chang
Miller, Marshall G.
Pistell, Paul J.
de Souza-Pinto, Nadja C.
Fishbein, Kenneth W.
Spencer, Richard G.
Liu, Yie
Pettan-Brewer, Christina
Ladiges, Warren C.
Wilson, David M.
author_facet McNeill, Daniel R.
Lin, Ping-Chang
Miller, Marshall G.
Pistell, Paul J.
de Souza-Pinto, Nadja C.
Fishbein, Kenneth W.
Spencer, Richard G.
Liu, Yie
Pettan-Brewer, Christina
Ladiges, Warren C.
Wilson, David M.
author_sort McNeill, Daniel R.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3185405
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-31854052011-10-04 XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility McNeill, Daniel R. Lin, Ping-Chang Miller, Marshall G. Pistell, Paul J. de Souza-Pinto, Nadja C. Fishbein, Kenneth W. Spencer, Richard G. Liu, Yie Pettan-Brewer, Christina Ladiges, Warren C. Wilson, David M. Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2011-10 2011-07-06 /pmc/articles/PMC3185405/ /pubmed/21737425 http://dx.doi.org/10.1093/nar/gkr280 Text en Published by Oxford University Press 2011. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genome Integrity, Repair and Replication
McNeill, Daniel R.
Lin, Ping-Chang
Miller, Marshall G.
Pistell, Paul J.
de Souza-Pinto, Nadja C.
Fishbein, Kenneth W.
Spencer, Richard G.
Liu, Yie
Pettan-Brewer, Christina
Ladiges, Warren C.
Wilson, David M.
XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
title XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
title_full XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
title_fullStr XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
title_full_unstemmed XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
title_short XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
title_sort xrcc1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185405/
https://www.ncbi.nlm.nih.gov/pubmed/21737425
http://dx.doi.org/10.1093/nar/gkr280
work_keys_str_mv AT mcneilldanielr xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT linpingchang xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT millermarshallg xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT pistellpaulj xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT desouzapintonadjac xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT fishbeinkennethw xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT spencerrichardg xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT liuyie xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT pettanbrewerchristina xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT ladigeswarrenc xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility
AT wilsondavidm xrcc1haploinsufficiencyinmicehaslittleeffectonagingbutadverselymodifiesexposuredependentsusceptibility