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The People of Tulane Cancer Center Research


Arthur J LustigArthur J. Lustig, Ph.D.
Professor of Biochemistry and Molecular Biology
Tulane Cancer Center Program Member

Contact Information
Email: alustig@tulane.edu
Phone: 504-988-3688
Address: 1700 Tulane Ave., LCRC, Room 809, New Orleans, LA 70112-2699

Biographical Narrative
Our laboratory is exploring the integrity of telomeres, the nucleoprotein structures at the end of eukaryotic chromosomes that are essential for chromosomal and genomic stability. Dysfunctional telomeres are associated with both oncogenic and aging states. We have developed genetic and physical tools to measure the regulation of telomere dynamics using a set of alleles defective at the alpha helical junction between two associating DNA repair proteins, Mre11 and Rad50. The homology of these proteins across evolution is likely to indicate a functional conservation as well. In the past, we have used the yeast Saccharomyces cerevisiae to investigate several major conserved yeast telomeric proteins. These proteins, which include Rap1 (yeast telomeric DNA binding protein), the Ku heterodimer (telomere end protection proteins), Ndj1 (meiotic telomere protein), and Sir3 (a key protein involved in telomere position effects [TPE]), have been invaluable in understanding telomere size homeostasis and TPE and the relationship between the two processes. We are currently using the mre11 alleles to understand a) the relationship between the use of telomerase and recombination-mediated telomere addition, b) the relationship between key proteins of semi-conservative DNA replication and the components regulating telomere homeostasis, and c) the structure function/relationship of the mutated proteins at the molecular and crystallographic level. These alleles also behave in an epigenetic and heritable fashion through an as yet unknown mechanism that may be some facet of telomere chromatin and/or end structure. Our investigations will provide us with the tools to examine the nature of this novel form of heritability that may also exert an influence on normal telomeres. Finally, telomere evolution defies simple patterns of continual changes in response to selective pressures. Rather, a significant number of conserved DNA repair and damage response proteins appear to serve differing functions in different organisms, leaving the possibility open that these common DNA repair factors can evolve rapidly to serve the needs of the particular system. We are probing, at the theoretical level, the possible underlying bases of this unusual evolutionary process. In addition, we are probing the mechanism of and therapeutic routes of recombination-based pathways (ALT) in both yeast and humans. In humans, ALT pathways are responsible for immortality in >15% of tumors. Our long-term goal is to increase our knowledge of the mechanism, efficiency, and regulation of telomere/telomere recombination that will subsequently provide the means for its manipulation. This information will be critical for the control of the ALT pathway of telomere addition in humans.

Selected Publications
Lustig, A.J., Kurtz, S., and Shore, D. 1990. Involvement of the silencer and UAS binding protein RAP1 in regulation of telomere length. Science 250, 549-553.

Kyrion, G., Boakye, K.A., and Lustig, A.J. 1992. C-terminal truncation of RAP1 results in the deregulation of telomere size, stability and function in Saccharomyces cerevisiae. Mol. Cell. Biol. 12, 5159-5173.

Kyrion, G., Liu, K., Liu, C., and Lustig, A.J. 1993. RAP1 and telomere structure regulate telomere position effects in Saccharomyces cerevisiae. Genes Dev. 7, 1146-1159.

Li, B. and Lustig, A.J. 1996. A novel mechanism for telomere size control in Saccharomyces cerevisiae. Genes Dev. 10, 1310-1326.

Polotnianka, R.M., Liu, J. and Lustig, A.J. 1998. The yeast Ku heterodimer is essential for protection against nucleolytic and recombinational activities. Current Biology, 8, 831-834.

Lustig, A.J. 1998. Mechanisms of silencing in Saccharomyces cerevisiae. Curr. Opin. Genet. Dev. 8, 233-239.

Lustig, A.J. 1999. Crisis intervention: The role of telomerase. Proc. Natl. Acad. Sci. U.S.A. 96, 3339-3341.

Bucholc, M., Park, Y., and Lustig, A.J. 2001. Intrachromatid excision of telomeric DNA as a mechanism for telomere size control in S. cerevisiae. Mol. Cell. Biol. 21, 6559-6573

Wyatt, H., Liaw, H., Green, G. R., and Lustig, A.J. 2003 Multiple role for Saccharomyces cerevisiae histone H2A in telomere position effect, spt suppression and DSB Repair, Genetics 164, 47-64.

Lustig, A.J. 2003. Opinion: Does telomere rapid deletion in yeast hold clues to catastrophic telomere loss in mammals? Nature Reviews Genetics, 4, 916-923 (perspective; peer-reviewed)

Joseph, I. Jia, D., and Lustig, A.J. 2005. Ndj1-dependent telomere size resetting in yeast meiosis, Current Biology, 15: 231-237

Williams B., Bhattacharyya M.K., Lustig, A.J. 2005. Mre11p Nuclease Activity is Dispensable for Telomeric Rapid Deletion. DNA Repair, 4: 994-1005

Bhattacharyya, M. and Lustig, A.J. 2006. Telomere dynamics in genome stability, TIBS. 31: 112-12.

Bhattacharyya, M.K, Kametra, K.M, and Lustig, A.J. (2008). Multiple Domains for Mre11 Monitoring of Telomere Damage, Chromosoma, 117: 357-366.

Lustig, A. (2009) Separating Effects of Telomere Size from the Mechanism of Elongation. EMBO J., (invited) 28:793-794.

Joseph, I.,Kumari, A., Bhattacharyya, M.K, Gao, H., Li, B and, Lustig, A.J. 2010. An mre11 Mutation that Promotes Telomere Recombination and an Efficient Bypass of Senescence, Genetics 185: 761-770.

Lustig, A.J. and Sgura, A. (2013) A new era of allele-specific diagnostics? Front Genet, 4: 134

Gao, H., Moss, D.L., Parke, C., Tatum, D., and Lustig, A.J. (2014) The Ctf18 Clamp Loader is Required for Telomere Stability in Telomerase- and mre11- Mutants. PLoS One 6, 88633.

 

1430 Tulane Ave, New Orleans, LA 70112 504-988-5263 medsch@tulane.edu