Tapas K. Hazra, Ph.D..Dr. Hazra

Assistant Professor, Dept. of Biochemistry and Molecular Biology, Sealy Center for Molecular Medicine

 

Research Activities

Our long-term research objective is to elucidate the detailed mechanisms of reactive oxygen species (ROS)-induced DNA damage repair and its regulation in mammalian cells, and to develop novel strategies for the prevention of ROS-induced carcinogenesis and disease pathologies. We have identified a family of mammalian DNA glycosylases for repair of oxidized bases, orthologous to the E.coli Nei, called NEIL (Nei- like)1 and NEIL2. We have characterized both proteins, and found that NEILs are distinct from the previously characterized DNA glycosylases (NTH1 and OGG1) in structural features, reaction mechanism and damage recognition.

Current projects in our lab

  1. Biochemical and Cellular characterization of NEIL2 interactome Although most of the DNA repair proteins are functional in isolation in vitro, in vivo all of them are associated with other proteins, forming complex (es) in a dynamic fashion. We have partially characterized the NEIL2-associated complex and identified stably interacting proteins. Characterizing the interacting interface of the proteins in repair complexes could help in designing therapeutic small molecules to prevent repair of genotoxic lesions induced during chemo/radiation therapy, and hence selectively sensitize cancer/diseased cells.
  2. Role of NEILs in the etiology of diseases We are characterizing naturally occurring polymorphic variants of NEILs. We are screening various disease tissue blots available either through collaborations or commercially. These polymorphisms, by altering structure of NEILs, activity and/or interaction with other proteins, may significantly influence the net level of function, and also ultimately affect the critical step in the cascade of events leading to disease.
  3. Structural studies of NEIL2 The tertiary structure of NEIL2 has not yet been elucidated; however, limited proteolytic digestion suggests that it has two major domains, the N-terminal domain (residues 1-198) and C-terminal domain (residues 199-331). The interacting regions in many proteins are dispensable for activity. However, not only is the C-terminal domain-containing Zn-finger motif essential, but the interacting domain, which is at the N-terminus, is also indispensable for activity. Thus elucidating the tertiary structure of full length NEIL2 and its individual domains may help in understanding its reaction mechanism and interacting interface with other proteins.

Selected Publications

1. 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 of modified bases in oxidatively damaged DNA. Proc Natl Acad Sci, 99:3523-3528 (Cover page article and special press release).

2. 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 (Accelerated publication).

3. 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 278:49679-49684.

4. 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. 22:6299-6309.

5. 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 *(Special press release by PNAS).

6. Wiederhold L, Leppard JB, Kedar P,Karimi-Busheri F, Rasouli-Nia A, Weinfeld M, Tomkinson AE, Izumi T, Prasad R, Wilson SH, Mitra S, Hazra TK. 2004. AP Endonuclease-independent DNA base excision repair in human cells. Mol Cell, 15:209-220.

7. Bhakat K K, Hazra TK. Mitra S. 2004. Acetylation of the Human DNA Glycosylase NEIL2 and Inhibition of Its Activity, Nucleic Acids Research, 32:3033-9.

8. Das A, Rajagopalan L, Mathura VS, Rigby SJ, Mitra S, Hazra TK. 2004. Identification of a Zinc finger domain in the human NEIL2 (Nei-like-2) protein. J. Biol. Chem. 279: 47132-8.

9. Bhakat KK, Mokkapati SK, Boldogh I, Hazra TK, Mitra S. 2006. Acetylation of human 8-oxoguanine-DNA glycosylase by p300 and its role in 8-oxoguanine repair in vivo. Mol Cell Biol 26: 1654-65.

10. Das A, Wiederhold L, Leppard JB, Kedar P, Prasad R, Wang H, Boldogh I, Karimi-Busheri F, Weinfeld M, Tomkinson AE, Wilson SH, Mitra S, Hazra TK. 2006 NEIL2-initiated, APE-independent repair of oxidized bases in DNA: Evidence for repair complex in human cell. DNA Repair (in press).