Arthur Lustig
Current Research Interests
1. Regulation of Eukaryotic Telomere Dynamics in Yeast
Our interest in telomeres, the specialized protein-DNA structures present at chromosomal termini, stems from their requirement for the stable inheritance of linear chromosomes. We have been particularly intrigued by four interconnected functions that are associated with telomeres in most eukaryotes: (a) telomere tract size homeostasis; (b) the regulation of recombination processes; (c) protection against deleterious recombination, fusions, and degradation processes; and (d) the formation of ‘closed’ structures in subtelomeric regions.
Our major interest is on the mechanism of telomere length homeostasis. Our previous studies uncovered one component of this process, telomeric rapid deletion (TRD). TRD excises over-elongated telomeric tracts to wild type sizes through intrachromatid recombination between the TG1-3 telomeric repeats and is likely to be involved in both mitotic telomere size control and meiotic resetting of telomere size. We are continuing to investigate the regulation and mechanism of recombinational mechanisms acting at the telomere with a focusing on TRD in the yeast Saccharomyces cerevisiae. Specifically, we are studying the physiologic and epigenetic control of TRD in mitotic and meiotic cells, the domain structure of Mre11 in context of TRD and the potential regulatory role of Mre11 in telomere recombination. This last goal has been fueled by our finding of an mre11 allele that confers a bypass both of the requirement for telomerase and of senescence most probably through the activation of a second promiscuous recombination pathway of elongation. Interestingly, the region that is mutated in this allele is highly conserved from yeast to humans. At the medical level, a dissection of homeostatic mechanisms is essential for the eventual manipulation of telomere size, strongly implicated as a major factor in oncogenesis.
2. The Characterization of Telomeric Heterochromatin
A second interest is in the structure and function of telomeric heterochromatin. We are currently taking two approaches to approach this problem. First, we are carrying out an in depth investigation of Sir3p, a key, but poorly understood, factor required for heterochromatin formation, as assayed by telomere position effects (TPE). Second, we have found that specific mutations at modifiable residues within the N-termini and C-termini of histone H2A have major effects on TPE particularly after DNA damage. We are currently studying the mechanism of histone H2A participation in TPE through an analysis of telomeric and subtelomeric chromatin structure in the various alleles and by the isolation of putative histone H2A interacting proteins in TPE. These studies are fundamental in identifying and characterizing the key players in heterochromatin formation and maintenance.Contact info: alustig@tulane.edu