Targeted deletion of mNth1 reveals a novel DNA repair enzyme activity.
DNA N-glycosylase/AP (apurinic/apyrimidinic) lyase enzymes of the endonuclease III family (nth in Escherichia coli and Nth1 in mammalian organisms) initiate DNA base excision repair of oxidized ring saturated pyrimidine residues. We generated a null mouse (mNth1(-/-)) by gene targeting. After almost 2 years, such mice exhibited no overt abnormalities. Tissues of mNth1(-/-) mice contained an enzymatic activity which cleaved DNA at sites of oxidized thymine residues (thymine glycol [Tg]). The activity was greater when Tg was paired with G than with A. This is in contrast to Nth1, which is more active against Tg:A pairs than Tg:G pairs. We suggest that there is a back-up mammalian repair activity which attacks Tg:G pairs with much greater efficiency than Tg:A pairs. The significance of this activity may relate to repair of oxidized 5-methyl cytosine residues (5meCyt). It was shown previously (S. Zuo, R. J. Boorstein, and G. W. Teebor, Nucleic Acids Res. 23:3239-3243, 1995) that both ionizing radiation and chemical oxidation yielded Tg from 5meCyt residues in DNA. Thus, this previously undescribed, and hence novel, back-up enzyme activity may function to repair oxidized 5meCyt residues in DNA while also being sufficient to compensate for the loss of Nth1 in the mutant mice, thereby explaining the noninformative phenotype.
Ocampo
Maria T A
MT
Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, New York 10016, USA.
Chaung
Wenren
W
Marenstein
Dina R
DR
Chan
Michael K
MK
Altamirano
Alvin
A
Basu
Ashis K
AK
Boorstein
Robert J
RJ
Cunningham
Richard P
RP
Teebor
George W
GW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001080:Apurinic Acid / Q000378:metabolism; D019757:Carbon-Oxygen Lyases / Q000032:analysis / Q000502:physiology*; D003433:Crosses, Genetic; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043224:Deoxyribonuclease (Pyrimidine Dimer); D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D029968:Escherichia coli Proteins; D005260:Female; D018390:Gene Targeting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D010641:Phenotype; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects
D029968:Escherichia coli Proteins; D001080:Apurinic Acid; D004706:Endodeoxyribonucleases; D043224:Deoxyribonuclease (Pyrimidine Dimer); C106403:NTH protein, E coli; C470703:Nthl1 protein, mouse; D019757:Carbon-Oxygen Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase