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TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions.

ABSTRACT: The Target Of Rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol-3-kinase-related kinases (PIKKs). TOR proteins are found at the core of two distinct evolutionarily conserved complexes, TORC1 and TORC2. Disruption of TORC1 or TORC2 results in characteristically dissimilar phenotypes. TORC1 is a major cell growth regulator, while the cellular roles of TORC2 are not well understood. In the fission yeast Schizosaccharomyces pombe, Tor1 is a component of the TORC2 complex, which is particularly required during starvation and various stress conditions. Our genome-wide gene expression analysis of Deltator1 mutants indicates an extensive similarity with chromatin structure mutants. Consistently, TORC2 regulates several chromatin-mediated functions, including gene silencing, telomere length maintenance, and tolerance to DNA damage. These novel cellular roles of TORC2 are rapamycin insensitive. Cells lacking Tor1 are highly sensitive to the DNA-damaging drugs hydroxyurea (HU) and methyl methanesulfonate, similar to mutants of the checkpoint kinase Rad3 (ATR). Unlike Rad3, Tor1 is not required for the cell cycle arrest in the presence of damaged DNA. Instead, Tor1 becomes essential for dephosphorylation and reactivation of the cyclin-dependent kinase Cdc2, thus allowing reentry into mitosis following recovery from DNA replication arrest. Taken together, our data highlight critical roles for TORC2 in chromatin metabolism and in promoting mitotic entry, most notably after recovery from DNA-damaging conditions. These data place TOR proteins in line with other PIKK members, such as ATM and ATR, as guardians of genome stability.

SUBMITTER: Schonbrun M

PROVIDER: S-EPMC2725747 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions.

Schonbrun Miriam M Laor Dana D López-Maury Luis L Bähler Jürg J Kupiec Martin M Weisman Ronit R

Molecular and cellular biology 20090622 16

The Target Of Rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol-3-kinase-related kinases (PIKKs). TOR proteins are found at the core of two distinct evolutionarily conserved complexes, TORC1 and TORC2. Disruption of TORC1 or TORC2 results in characteristically dissimilar phenotypes. TORC1 is a major cell growth regulator, while the cellular roles of TORC2 are not well understood. In the fission yeast Schizosaccharomyces pombe, Tor1 is a component of ...[more]

PMID: 19546237

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Project description:BackgroundTelomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.MethodsWe performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.ResultsWe found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use ≥ 5 yrs after adjusting for age of blood donation and race and ethnicity.ConclusionsWe found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.

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TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions.

Publications

TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions.

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