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Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate.
- Source :
-
Cancer research [Cancer Res] 2006 Aug 01; Vol. 66 (15), pp. 7460-5. - Publication Year :
- 2006
-
Abstract
- This study uses a base excision repair (BER)-deficient model, the DNA polymerase beta heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged beta-pol(+/-) mice express 50% less beta-pol transcripts and protein (P < 0.05) than aged beta-pol(+/+) mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in beta-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged beta-pol(+/-) mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of beta-pol(+/-) mice exhibited lymphoid hyperplasia, whereas none of the beta-pol(+/+) exhibited this phenotype. beta-pol(+/-) mice were also more likely to develop adenocarcinoma (2.7-fold increase; P < 0.05) and more likely to develop multiple tumors, as 20% of the beta-pol(+/-) animals died bearing multiple tumors compared with only 5% of the beta-pol(+/+) animals (P < 0.05). In spite of accelerated tumor development, no gross effect of beta-pol heterozygosity was seen with respect to life span. However, the survival curves for the beta-pol(+/+) and beta-pol(+/-) mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P < 0.05) acceleration of the age-dependent mortality rate in beta-pol(+/-) mice. Thus, the beta-pol(+/-) mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis.
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 66
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 16885342
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-06-1177