The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation.
Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology.
Hofseth
Lorne J
LJ
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Khan
Mohammed A
MA
Ambrose
Mark
M
Nikolayeva
Olga
O
Xu-Welliver
Meng
M
Kartalou
Maria
M
Hussain
S Perwez
SP
Roth
Richard B
RB
Zhou
Xiaoling
X
Mechanic
Leah E
LE
Zurer
Irit
I
Rotter
Varda
V
Samson
Leona D
LD
Harris
Curtis C
CC
D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D020137:Base Pair Mismatch; D003093:Colitis, Ulcerative / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D016368:Frameshift Mutation; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D020014:K562 Cells; D018895:Microsatellite Repeats; D013997:Time Factors; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C021565:3-methyladenine-DNA glycosylase; C085108:APEX1 protein, human