Present Position and Address

6.154 Medical Research Bldg.
Mail Route:1079
Telephone: (409) 772-2156
Fax: (409) 747-8608
Email: tkhazra@utmb.edu

B.S. 1982 Calcutta University, India
M.S. 1984 Calcutta University, India
Ph.D. 1992 Jadavpur University, Calcutta

RESEARCH INTERESTS:

Our broad area of research interest is the repair of oxidative DNA damage repair in mammalian cells. Oxidatively induced DNA lesions have been implicated in the etiology of many diseases (including cancer) and in aging. Among many base lesions induced by reactive oxygen species (ROS), 5-hydroxyuracil (5-OHU) and 8-oxoguanine (8-oxoG) are believed to be responsible for the majority of ROS-induced GC to AT and GC to TA mutations respectively. Repair of oxidatively damaged bases in all organisms occurs primarily via the DNA base excision repair (BER) pathway, initiated with their excision by DNA glycosylases. Only two mammalian DNA glycosylases, OGG1 and NTH1 of E. coli Nth-type, were previously thought to excise most of the oxidatively damaged lesions. We have recently discovered and partially characterized two human orthologs of E.coli Nei, and named them NEIL (Nei-like)-1 and 2. The NEILs are distinct from NTH1 and OGG1 in structural features and reaction mechanism but act on many of the same substrates. After base excision, Nth-type DNA glycosylases cleave the DNA strand at the AP-site to produce a 3’-aß unsaturated aldehyde whereas Nei-type enzymes produce 3’-phosphate terminus. E. coli APEs efficiently remove both types of termini in addition to cleaving the AP site to generate a 3’OH, the primer terminus for repair DNA synthesis. In contrast, the mammalian APE, APE1, which has an essential role in NTH1/OGG1-initiated BER, has very poor 3’-phosphatase activity and is dispensable for NEIL-initiated BER. Polynucleotide kinase (PNK), present in mammalian cells but not in E.coli, removes the 3’ phosphate, and is involved in NEIL-initiated BER. NEILs show a unique preference for excising lesions from a DNA bubble, while most DNA glycosylases, including OGG1 and NTH1, are active only with duplex DNA. This dichotomy in the preference of NEILs and NTH1/OGG1 for bubble vs. duplex DNA substrates raised the possibility that NEILs function in repair of base lesions present in the transcription bubble, transiently generated ahead of the growing RNA chain. A lack of phenotype and the efficient repair of 8-oxoG and thymine glycol from the transcribed sequences in DNA of OGG1 and NTH1-null mouse cells support this hypothesis. Thus NEILs may play a unique role in maintaining the functional integrity of mammalian genomes. The implications of this differential activity of NEIL1 and -2 in duplex vs. bubble DNA are currently under investigation.

1. Hazra TK, Izumi T, Venkataraman R, Kow YK, Dizdaroglu M, Mitra S. 2000. Characterization of a novel 8-oxoguanine-DNA glycosylase activity in E. coli and identification of the enzyme as endonuclease VIII. J. Biol. Chem. 275:27762-27767.
2. Mitra S, Boldogh I, Izumi T, Hazra TK. 2001 Complexities of the DNA base excision repair pathway for repair of oxidative DNA damage. Environ Mol Mutagen 38: 180-190.
3. Hill JW, Hazra TK, Izumi T, Mitra S. 2001. Stimulation of human 8-oxoguanine-DNA glycosylase by AP-endonuclease: Potential co-ordination of the initial steps in base excision repair. Nucl. Acids Res. 29:430-438.
4. Hazra TK, Muller JG, Manuel RC, Burrows CJ, Lloyd RS, Mitra S. 2001. Repair of hydantoins, one electron oxidation products of 8-oxoguanine, by DNA glycosylases of Escherichia coli. Nucl. Acids Res. 29:1967-1974.
5. Hazra TK, Izumi T, Boldogh I, Imhoff B, Kow YW, Jaruga P, Dizdaroglu M, Mitra S. 2002 Identification and characterization of a human DNA glycosylase for repair in modified bases in oxidatively damaged DNA. Proc Natl Acad Sci, 99:3523-3528.
6. Hazra TK, Kow YW, Hatahet Z, Imhoff, B, Boldogh I, Mokkapati SK, Mitra S, Izumi T 2002. Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived bases. J.Biol.Chem, 277:30417-30420
7. Szczesny B., Hazra TK, Papaconstantinou J, Mitra S, Boldogh I. 2003. Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci, 100: 10670-5.
8. Dou H, Mitra S, Hazra TK. 2003. Repair of oxidized bases from DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2. J. Biol. Chem (in press).
9. Bhakat KK, Izumi T, Yang SH, Boldogh I, Hazra TK, Mitra S. 2003. Acetylation of human AP- endonuclease 1 (APE1/Ref-1) and repression of the parathyroid hormone gene. EMBO J. (in press).