HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 35, 36504-36513, August 27, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/35/36504    most recent M405185200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cabelof, D. C. Articles by Heydari, A. R. Search for Related Content PubMed PubMed Citation Articles by Cabelof, D. C. Articles by Heydari, A. R. Social Bookmarking                      What's this?

Imbalanced Base Excision Repair in Response to Folate Deficiency Is Accelerated by Polymerase Haploinsufficiency^*

Diane C. Cabelof, Julian J. Raffoul, Jun Nakamura, Diksha Kapoor, Hala Abdalla, and Ahmad R. Heydari¶

From the Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan 48202 and the Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599

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 (-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 -pol and mount a BER response when folate is deficient is causative in the accumulation of toxic repair intermediates, -pol-haploin-sufficient mice subjected to folate deficiency displayed additional increases in DNA single strand breaks (52% increase, p < 0.05) as well as accumulation in aldehydic DNA lesions (38% increase, p < 0.01). Since young -polhaploinsufficient mice do not spontaneously exhibit increased levels of these repair intermediates, these data demonstrate that folate deficiency and -pol haploinsufficiency interact to increase the accumulation of DNA damage. In addition to establishing a direct role for -pol in the phenotype expressed by folate deficiency, these data are also consistent with the concept that repair of uracil and abasic sites is more efficient than repair of oxidized bases.

Received for publication, May 10, 2004 , and in revised form, June 18, 2004.

^* This work was supported by National Institutes of Health Grant 1R21-DK62256 (to A. R. H.) and a grant from the American Institute for Cancer Research (to A. R. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence and reprint requests should be addressed: Dept. of Nutrition & Food Science, 3009 Science Hall, Wayne State University, Detroit, MI 48202. Tel.: 313-577-2753; Fax: 313-577-8616; E-mail: ahmad.heydari{at}wayne.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Liu, Y. Ge, D. C. Cabelof, A. Aboukameel, A. R. Heydari, R. Mohammad, and L. H. Matherly Structure and Regulation of the Murine Reduced Folate Carrier Gene: IDENTIFICATION OF FOUR NONCODING EXONS AND PROMOTERS AND REGULATION BY DIETARY FOLATES J. Biol. Chem., February 18, 2005; 280(7): 5588 - 5597. [Abstract] [Full Text] [PDF]

				G. P Oakley and J. S Mandel Folic acid fortification remains an urgent health priority BMJ, December 11, 2004; 329(7479): 1376 - 1376. [Full Text] [PDF]