Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate.
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.
Cabelof
Diane C
DC
Karmanos Cancer Institute, Developmental Therapeutics Program, Wayne State University School of Medicine, 110 East Warren, Detroit, MI 48201, USA. d.cabelof@wayne.edu
Ikeno
Yuji
Y
Nyska
Abraham
A
Busuttil
Rita A
RA
Anyangwe
Njwen
N
Vijg
Jan
J
Matherly
Larry H
LH
Tucker
James D
JD
Wilson
Samuel H
SH
Richardson
Arlan
A
Heydari
Ahmad R
AR
D000367:Age Factors; D000818:Animals; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D006238:Haploidy; D008136:Longevity; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics*; D012307:Risk Factors
D019951:DNA Polymerase beta