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

Diane C. Cabelof, Yuji Ikeno, Abraham Nyska, Rita A. Busuttil, Njwen Anyangwe, Jan Vijg, Larry H. Matherly, James D. Tucker, Samuel H. Wilson, Arlan Richardson, Ahmad R. Heydari

Research output: Contribution to journalArticle

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Abstract

This study uses a base excision repair (BER)-deficient model, the DNA polymerase β heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged β-pol+/- mice express 50% less β-pol transcripts and protein (P < 0.05) than aged β-pol+/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in β-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged β-pol+/- mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of β-pol+/- mice exhibited lymphoid hyperplasia, whereas none of the β-pol+/+ exhibited this phenotype. β-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 β-pol+/- animals died bearing multiple tumors compared with only 5% of the β-pol+/+ animals (P < 0.05). In spite of accelerated tumor development, no gross effect of β-pol heterozygosity was seen with respect to life span. However, the survival curves for the β-pol+/+ and β-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 β-pol +/- mice. Thus, the β-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.

Original languageEnglish (US)
Pages (from-to)7460-7465
Number of pages6
JournalCancer Research
Volume66
Issue number15
DOIs
StatePublished - Aug 1 2006

Fingerprint

Haploinsufficiency
DNA-Directed DNA Polymerase
Mortality
Neoplasms
DNA Repair
pol Gene Products
Maintenance
Value of Life
Mutation Rate
Hyperplasia
Lymphoma
Carcinogenesis
Adenocarcinoma
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cabelof, D. C., Ikeno, Y., Nyska, A., Busuttil, R. A., Anyangwe, N., Vijg, J., ... Heydari, A. R. (2006). Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate. Cancer Research, 66(15), 7460-7465. https://doi.org/10.1158/0008-5472.CAN-06-1177

Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate. / Cabelof, Diane C.; Ikeno, Yuji; Nyska, Abraham; Busuttil, Rita A.; Anyangwe, Njwen; Vijg, Jan; Matherly, Larry H.; Tucker, James D.; Wilson, Samuel H.; Richardson, Arlan; Heydari, Ahmad R.

In: Cancer Research, Vol. 66, No. 15, 01.08.2006, p. 7460-7465.

Research output: Contribution to journalArticle

Cabelof, DC, Ikeno, Y, Nyska, A, Busuttil, RA, Anyangwe, N, Vijg, J, Matherly, LH, Tucker, JD, Wilson, SH, Richardson, A & Heydari, AR 2006, 'Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate', Cancer Research, vol. 66, no. 15, pp. 7460-7465. https://doi.org/10.1158/0008-5472.CAN-06-1177
Cabelof, Diane C. ; Ikeno, Yuji ; Nyska, Abraham ; Busuttil, Rita A. ; Anyangwe, Njwen ; Vijg, Jan ; Matherly, Larry H. ; Tucker, James D. ; Wilson, Samuel H. ; Richardson, Arlan ; Heydari, Ahmad R. / Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate. In: Cancer Research. 2006 ; Vol. 66, No. 15. pp. 7460-7465.
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AU - Ikeno, Yuji

AU - Nyska, Abraham

AU - Busuttil, Rita A.

AU - Anyangwe, Njwen

AU - Vijg, Jan

AU - Matherly, Larry H.

AU - Tucker, James D.

AU - Wilson, Samuel H.

AU - Richardson, Arlan

AU - Heydari, Ahmad R.

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N2 - This study uses a base excision repair (BER)-deficient model, the DNA polymerase β heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged β-pol+/- mice express 50% less β-pol transcripts and protein (P < 0.05) than aged β-pol+/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in β-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged β-pol+/- mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of β-pol+/- mice exhibited lymphoid hyperplasia, whereas none of the β-pol+/+ exhibited this phenotype. β-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 β-pol+/- animals died bearing multiple tumors compared with only 5% of the β-pol+/+ animals (P < 0.05). In spite of accelerated tumor development, no gross effect of β-pol heterozygosity was seen with respect to life span. However, the survival curves for the β-pol+/+ and β-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 β-pol +/- mice. Thus, the β-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.

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