Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate

Cancer Res. 2006 Aug 1;66(15):7460-5. doi: 10.1158/0008-5472.CAN-06-1177.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • DNA Damage
  • DNA Polymerase beta / genetics*
  • DNA Polymerase beta / metabolism
  • DNA Repair
  • Haploidy
  • Longevity
  • Male
  • Mice
  • Neoplasms, Experimental / enzymology*
  • Neoplasms, Experimental / genetics*
  • Risk Factors


  • DNA Polymerase beta