Creation of a fully functional human chimeric DNA repair protein. Combining O6-methylguanine DNA methyltransferase (MGMT) and AP endonuclease (APE/redox effector factor 1 (Ref 1)) DNA repair proteins.

The Journal of Biological Chemistry
W K HansenM R Kelley

Abstract

A dose-limiting toxicity of certain chemotherapeutic alkylating agents is their toxic effects on nontarget tissues such as the bone marrow. To overcome the myelosuppression observed by chemotherapeutic alkylating agents, one approach is to increase the level of DNA repair proteins in hematopoietic stem and progenitor cells. Toward this goal, we have constructed a human fusion protein consisting of O6-methylguanine DNA methyltransferase coupled with an apurinic endonuclease, resulting in a fully functional protein for both O6-methylguanine and apurinic/apyrimidinic (AP) site repair as determined by biochemical analysis. The chimeric protein protected AP endonuclease-deficient Escherichia coli cells against methyl methanesulfonate and hydrogen peroxide (H2O2) damage. A retroviral construct expressing the chimeric protein also protected HeLa cells against 1,3-bis(2-chloroethyl)-1-nitrosourea and methyl methanesulfonate cytotoxicity either when these agents were used separately or in combination. Moreover, as predicted from previous analysis, truncating the amino 150 amino acids of the apurinic endonuclease portion of the O6-methylguanine DNA methyltransferase-apurinic endonuclease protein resulted in the retention of O6-methylguan...Continue Reading

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Citations

Oct 6, 2000·Mutation Research·A R EvansM R Kelley
Apr 18, 2000·Mutation Research·A E Pegg
Apr 12, 2000·European Journal of Biochemistry·G Frosina
Sep 14, 2001·Antioxidants & Redox Signaling·M R Kelley, S H Parsons
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Jan 31, 2002·Annual Review of Medicine·Punit D WadhwaStanton L Gerson
Jun 12, 2013·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Liang Yin, Carl E Bauer
Nov 6, 2003·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Jing LanJun Chen
Mar 11, 2000·Environmental and Molecular Mutagenesis·M Limp-Foster, M R Kelley
Jan 6, 2018·Biomedicines·Ilya O VelegzhaninovOlesya M Vakhrusheva
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Nov 29, 2013·American Journal of Physiology. Gastrointestinal and Liver Physiology·Hiroyuki NagoyaChoitsu Sakamoto
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Jan 9, 2010·Cancer Treatment Reviews·Rachel Abbotts, Srinivasan Madhusudan

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