Arthur J Lustig | Tulane University (original) (raw)

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Papers by Arthur J Lustig

Nature Reviews Genetics, Nov 1, 2003

Nature Reviews Genetics, Apr 1, 2004

Frontiers in Genetics, Apr 6, 2016

Trends in Cell Biology, May 1, 2019

Biochemistry, Jan 19, 1982

We have analyzed the catabolite regulation of cytochrome oxidase by assaying changes in the synth... more We have analyzed the catabolite regulation of cytochrome oxidase by assaying changes in the synthesis of precursors of the nuclear-coded peptides (IV--VII) of cytochrome c oxidase in an in vitro reticulocyte cell-free system programmed with RNA isolated from cells grown in either glucose or raffinose. As a first step, we have characterized antibodies which bind to the precursors of subunits V and VI. Initial translation products for subunits IV and VII have also been tentatively identified by utilizing these antibodies. The messenger RNAs coding for the precursors of the nuclear-coded subunits fall in the expected size range of 8--15 S. Catabolite repression of the nuclear-coded oxidase peptides appears to be regulated by the abundance of their messenger RNAs. Translation of messenger RNA isolated from yeast cells grown on glucose indicates a coordinate and uniform increase in precursor synthesis during glucose derepression. In contrast, when RNA isolated from raffinose (derepressed) grown cells is used to direct cell-free translation, precursor abundance is high throughout growth, although the synthesis of some of the species changes in a complex pattern of ratio and abundance. These data indicate that the abundance of the messengers for the nuclear-coded precursors is regulated in a fashion dependent on the physiologic state of the cell.

Current Biology, Jul 1, 1998

Proceedings of the National Academy of Sciences of the United States of America, Mar 30, 1999

Frontiers in Genetics, Feb 10, 2016

Genetics, Jul 1, 2010

Preventing the formation of dysfunctional telomeres is essential for genomic stability. In most o... more Preventing the formation of dysfunctional telomeres is essential for genomic stability. In most organisms, the ribo-nucleoprotein reverse transcriptase telomerase is responsible for telomere GT-strand elongation. However, in telomerase-negative cells, low-frequency recombination mechanisms can avert lethality by elongating critically short telomeres. This study focuses on the involvement of the budding yeast Mre11 in telomere recombination and homeostasis. We have identified a novel allele of MRE11, mre11-A470T, that, in telomerase-positive cells, confers a semidominant decrease in telomere size and a recessive defect in telomere healing. In addition, mutant cells lack normal telomere size homeostasis. Telomerase-negative mre11-A470T cells display a Rad51-dependent bypass of replicative senescence via induction of a highly efficient type I-related recombination pathway termed type IA. The type IA pathway involves an amplification of subtelomeric Y9 elements, coupled with elongated and more heterogeneous telomere tracts relative to the short telomere size of type I survivors. The data have led us to propose the involvement of break-induced replication in telomere expansion. The differing phenotypes elicited by the mre11-A470T mutants in telomerase-positive and telomerase-negative cells have also led us to speculate that the telomere end structure may be modified differentially in mre11-A470T cells, directing the telomere into specific pathways.

Molecular Cell, May 1, 2003

Genes & Development, Jun 1, 1996

One of the central requirements for eukaryotic chromosome stability is the maintenance of the sim... more One of the central requirements for eukaryotic chromosome stability is the maintenance of the simple sequence tracts at telomeres. In this study, we use genetic and physical assays to reveal the nature of a novel mechanism by which telomere length is controlled. This mechanism, telomeric rapid deletion (TRD), is capable of reducing elongated telomeres to wild-type tract length in an apparently single-division process. The deletion of telomeres to wild-type lengths is stimulated by the hprl mutation, suggesting that TRD in these cells is the consequence of an intrachromatid pathway. Paradoxically, TRD is also dependent on the lengths of the majority of nonhomologous telomeres in the cell. Defects in the chromatin-organizing protein Sir3p increase the rate of Aprl-induced rapid deletion and specifically change the spectrum of rapid deletion events. We propose a model in which interactions among telosomes of nonhomologous chromosomes form higher order complexes that restrict the access of the intrachromatid recombination machinery to telomeres. This mechanism of size control is distinct from that mediated through telomerase and is likely to maintain telomere length within a narrow distribution.

DNA Repair, Aug 1, 2005

Telomeric rapid deletion (TRD) is an intrachromatid recombination process that truncates over-elo... more Telomeric rapid deletion (TRD) is an intrachromatid recombination process that truncates over-elongated telomeres to the genetically determined average telomere length. We have proposed that TRD is initiated by invasion of the 3 G-rich overhang into centromere-proximal telomere sequence, forming an intermediate that leads to excision of the distal telomere tract. TRD efficiency is dependent on Mre11p and Rad50p, two members of the widely conserved Mre11p/Rad50p/Xrs2p (MRX) complex. To investigate the role of Mre11p in TRD, we conducted a structure/function analysis by testing the TRD rate and precision of mutations within known functional domains. We analyzed 12 alleles that disrupt different Mre11p activities. Surprisingly, mutations in essential residues of the nuclease domain do not inhibit TRD, effectively ruling out nuclease activity as the source of the Mre11p requirement. Interestingly, loss of Exo1p alone or loss of Exo1p in an Mre11 nuclease deficient background does not eliminate TRD, suggesting the presence of an additional nuclease. Second, deletion of DNA binding sites A (residues 410-420) and B (residues 644-692) actually enhances the TRD rate. Even deletion of both DNA binding domains does not abrogate TRD, although its kinetics and precision are variable. This suggests altered DNA binding or a conformational defect in the MRX complex may affect the rate of TRD product formation and indicates that the DNA binding sites formally act as repressors of TRD. Remarkably, the H213Y allele (nuclease motif IV) confers an extraordinarily rapid kinetics, with the vast majority of elongated telomeres deleted imprecisely in a single round of subculturing. In striking contrast, the P162S allele that confers dissolution of the complex also exhibits the null phenotype. These data suggest that Mre11p can act as a positive and negative regulator of TRD in context of the MRX complex that is essential for TRD.

Cellular and Molecular Life Sciences, 2007

PLOS ONE, Feb 12, 2014

The function of the replication clamp loaders in the semi-conservative telomere replication and t... more The function of the replication clamp loaders in the semi-conservative telomere replication and their relationship to telomerase-and recombination mechanisms of telomere addition remains ambiguous. We have investigated the variant clamp loader Ctf18 RFC (Replication Factor C). To understand the role of Ctf18 at the telomere, we first investigated genetic interactions after loss of Ctf18 and TLC1 (the yeast telomerase RNA). We find that the tlc1n ctf18n double mutant confers a rapid .1000-fold decrease in viability. The rate of loss was similar to the kinetics of cell death in rad52n tlc1n cells. However, the Ctf18 pathway is distinct from Rad52, required for the repair of DSBs, as demonstrated by the synthetic lethality of rad52n tlc1n ctf18n triple mutants. These data suggest that each mutant elicits non-redundant defects acting on the same substrate. Second, interactions of the yeast hyper-recombinational mutant, mre11A470T, with ctf18n confer a synergistic cold sensitivity. The phenotype of these double mutants ultimately results in telomere loss and the generation of recombinational survivors. We observed a similar synergism between single mutants that led to hypersensitivity to the DNA alkylating agent, methane methyl sulphonate (MMS), the replication fork inhibitor hydroxyurea (HU), and to a failure to separate telomeres of sister chromatids. Hence, ctf18n and mre11A470T act in different pathways on telomere substrates for multiple phenotypes. The mre11A470T cells also displayed a DNA damage response (DDR) at 15uC but not at 30uC while ctf18n mutants conferred a constitutive DDR activity. Both the 15uC DDR pattern and growth rate were reversible at 30uC and displayed telomerase activity in vivo. We hypothesize that Ctf18 confers protection against stalling and/or breaks at the replication fork in cells that either lack, or are compromised for, telomerase activity. This Ctf18-based function is likely to contribute another level to telomere size homeostasis.