Imbalanced base excision repair in response to folate deficiency is accelerated by polymerase beta haploinsufficiency

The Journal of Biological Chemistry
Diane C CabelofAhmad R Heydari

Abstract

The mechanism by which folate deficiency influences carcinogenesis is not well established, but a phenotype of DNA strand breaks, mutations, and chromosomal instability suggests an inability to repair DNA damage. To elucidate the mechanism by which folate deficiency influences carcinogenicity, we have analyzed the effect of folate deficiency on base excision repair (BER), the pathway responsible for repairing uracil in DNA. We observe an up-regulation in initiation of BER in liver of the folate-deficient mice, as evidenced by an increase in uracil DNA glycosylase protein (30%, p < 0.01) and activity (31%, p < 0.05). However, no up-regulation in either BER or its rate-determining enzyme, DNA polymerase beta (beta-pol) is observed in response to folate deficiency. Accordingly, an accumulation of repair intermediates in the form of DNA single strand breaks (37% increase, p < 0.03) is observed. These data indicate that folate deficiency alters the balance and coordination of BER by stimulating initiation without subsequently stimulating the completion of repair, resulting in a functional BER deficiency. In directly establishing that the inability to induce beta-pol and mount a BER response when folate is deficient is causative in t...Continue Reading

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Citations

Apr 21, 2010·The Journal of Biological Chemistry·Lisa F Ventrella-LucenteAhmad R Heydari
Dec 14, 2004·BMJ : British Medical Journal·Godfrey P Oakley, Jack S Mandel
Oct 25, 2012·Journal of Oncology·Rita RosatiDiane C Cabelof
Oct 31, 2014·Carcinogenesis·Boris M BrenermanDavid M Wilson
Sep 29, 2011·Cellular and Molecular Life Sciences : CMLS·Diane C Cabelof
Jan 24, 2012·Clinical Genetics·F Migheli, L Migliore
Mar 27, 2015·Cellular and Molecular Life Sciences : CMLS·Na LiBevin P Engelward
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Aug 18, 2005·Environmental and Molecular Mutagenesis·Diane C CabelofAhmad R Heydari
Feb 7, 2012·Mechanisms of Ageing and Development·Kirk W SimonDiane C Cabelof
Jul 5, 2008·Biochemical Pharmacology·Sondra H BergerMichael D Wyatt
Nov 13, 2010·Free Radical Biology & Medicine·Archana UnnikrishnanAhmad R Heydari

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