Tapas K. Hazra, Ph.D.

Publications (Pubmed)

Affiliations: Department of Biochemistry & Molecular Biology
Tel: (409) 772-2156
Fax: (409) 747-8608
tkhazra@utmb.edu
Route: 1079
6.136D MRB

 

 

 

Tapas K. Hazra, Ph.D.

Associate Professor

Our broad area of research interest is the repair of oxidative DNA damage 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 are involved in transcription and/or replication associated repair and thus inactivation of these two enzymes should have a profound effect in vivo . 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.