TY - JOUR
T1 - Susceptibility to intestinal tumorigenesis in folate-deficient mice may be influenced by variation in one-carbon metabolism and DNA repair
AU - Knock, Erin
AU - Deng, Liyuan
AU - Krupenko, Natalia
AU - Mohan, Ryan D.
AU - Wu, Qing
AU - Leclerc, Daniel
AU - Gupta, Sapna
AU - Elmore, C. Lee
AU - Kruger, Warren
AU - Tini, Marc
AU - Rozen, Rima
N1 - Copyright © 2011 Elsevier Inc. All rights reserved.
PY - 2011/11
Y1 - 2011/11
N2 - Low dietary folate is associated with increased risk of colorectal cancer. In earlier work, we showed that folate deficiency induced intestinal tumors in BALB/c but not C57Bl/6 mice through increased dUTP incorporation into DNA with consequent DNA damage. To determine whether strain differences between one-carbon metabolism and DNA repair pathways could contribute to increased tumorigenesis in BALB/c mice, we measured amino acids and folate in the normal intestinal tissue of both strains fed a control diet or a folate-deficient diet. We also determined the expression of critical folate-metabolizing enzymes and several DNA repair enzymes. BALB/c mice had lower intestinal serine (major cellular one-carbon donor), methionine and total folate than C57Bl/6 mice under both dietary conditions. BALB/c mice had higher messenger RNA and protein levels of three folate-interconverting enzymes: trifunctional methyleneTHF (5,10-methylenetetrahydrofolate) dehydrogenase-methenylTHF cyclohydrolase-formylTHF (10-formyltetrahydrofolate) synthetase 1, bifunctional methyleneTHF dehydrogenase-methenylTHF cyclohydrolase and methylenetetrahydrofolate reductase. This pattern of expression could limit the availability of methyleneTHF for conversion of dUMP to dTMP. BALB/c mice also had higher levels of uracil DNA glycosylase 2 protein without an increase in the rate-limiting DNA polymerase β enzyme, compared with C57Bl/6 mice. We conclude that BALB/c mice may be more prone to DNA damage through decreased amounts of one-carbon donors and the diversion of methyleneTHF away from the conversion of dUMP to dTMP. In addition, incomplete excision repair of uracil in DNA could lead to accumulation of toxic repair intermediates and promotion of tumorigenesis in this tumor-susceptible strain.
AB - Low dietary folate is associated with increased risk of colorectal cancer. In earlier work, we showed that folate deficiency induced intestinal tumors in BALB/c but not C57Bl/6 mice through increased dUTP incorporation into DNA with consequent DNA damage. To determine whether strain differences between one-carbon metabolism and DNA repair pathways could contribute to increased tumorigenesis in BALB/c mice, we measured amino acids and folate in the normal intestinal tissue of both strains fed a control diet or a folate-deficient diet. We also determined the expression of critical folate-metabolizing enzymes and several DNA repair enzymes. BALB/c mice had lower intestinal serine (major cellular one-carbon donor), methionine and total folate than C57Bl/6 mice under both dietary conditions. BALB/c mice had higher messenger RNA and protein levels of three folate-interconverting enzymes: trifunctional methyleneTHF (5,10-methylenetetrahydrofolate) dehydrogenase-methenylTHF cyclohydrolase-formylTHF (10-formyltetrahydrofolate) synthetase 1, bifunctional methyleneTHF dehydrogenase-methenylTHF cyclohydrolase and methylenetetrahydrofolate reductase. This pattern of expression could limit the availability of methyleneTHF for conversion of dUMP to dTMP. BALB/c mice also had higher levels of uracil DNA glycosylase 2 protein without an increase in the rate-limiting DNA polymerase β enzyme, compared with C57Bl/6 mice. We conclude that BALB/c mice may be more prone to DNA damage through decreased amounts of one-carbon donors and the diversion of methyleneTHF away from the conversion of dUMP to dTMP. In addition, incomplete excision repair of uracil in DNA could lead to accumulation of toxic repair intermediates and promotion of tumorigenesis in this tumor-susceptible strain.
KW - Aminohydrolases/metabolism
KW - Animals
KW - Colorectal Neoplasms/genetics
KW - DNA Methylation
KW - DNA Polymerase beta/metabolism
KW - DNA Repair/genetics
KW - Diet
KW - Folic Acid Deficiency/complications
KW - Folic Acid/metabolism
KW - Formate-Tetrahydrofolate Ligase/metabolism
KW - Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism
KW - Methylenetetrahydrofolate Reductase (NADPH2)/genetics
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Multienzyme Complexes/metabolism
KW - RNA, Messenger/metabolism
KW - Serine/metabolism
KW - Tetrahydrofolates/metabolism
KW - Uracil-DNA Glycosidase/metabolism
UR - http://www.scopus.com/inward/record.url?scp=80054061671&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000296268500005&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1016/j.jnutbio.2010.07.015
DO - 10.1016/j.jnutbio.2010.07.015
M3 - Article
C2 - 21193302
SN - 0955-2863
VL - 22
SP - 1022
EP - 1029
JO - Journal of Nutritional Biochemistry
JF - Journal of Nutritional Biochemistry
IS - 11
ER -