Aging alters folate homeostasis and DNA damage response in colon.
The risk for developing colorectal cancer increases exponentially with age. We demonstrate that spontaneous loss of folate in the colon results in DNA damage accumulation and aberrant DNA damage responses that may contribute to the increased genomic instability and cancer risk in colon. We find greater than 2-fold changes in the expression of folate-absorption and folate retention genes within the colonocyte, demonstrating that with age the colon is able to induce expression of appropriate genes in response to limiting folate status. However, we also find that aging results in spontaneous accumulation of uracil in colon DNA, indicating that folate status is not fully restored by the increase in folate absorption. Expression of uracil-excising enzymes (Ung and Smug) are induced in response to uracil accumulation, and with age we see an approximate 3-fold increase in the level of expression that is matched by a corresponding increase in DNA polymerase β expression. In further evaluating the DNA damage response, we investigated p53 localization and function and find abundant p53 levels, with p53 sequestered almost entirely in the cytoplasm. To determine whether cytoplasmic localization might impact p53 transactivation function, we conducted an unbiased screen of p53-target genes and found that age substantially alters expression of p53-target genes.
Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA.
Kirk W
KW
Simon
Hongzhi
H
Ma
Alan A
AA
Dombkowski
Diane C
DC
Cabelof
D000375:Aging; D000818:Animals; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism*; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012306:Risk; D013997:Time Factors; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014498:Uracil / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D014498:Uracil; D004247:DNA; D005492:Folic Acid