SUMOylation regulates telomere length homeostasis by targeting Cdc13

Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 07/2011; 18(8):920-6. DOI: 10.1038/nsmb.2100
Source: PubMed


Telomere length homeostasis is an important aspect of telomere biology. Here, we show that SUMOylation limits telomere length and targets multiple telomere proteins in Saccharomyces cerevisiae. A main target is Cdc13, which both positively and negatively regulates telomerase and confers end protection. We demonstrate that Cdc13 SUMOylation restrains telomerase functions by promoting Cdc13 interaction with the telomerase inhibitor Stn1 without affecting end protection. Mutation of the Cdc13 SUMOylation site (cdc13-snm) lengthens telomeres and reduces the Stn1 interaction, whereas Cdc13-SUMO fusion has the opposite effects. cdc13-snm's effect on telomere length is epistatic with stn1, but not with yku70, tel1 or est1 alleles, and is suppressed by Stn1 overexpression. Cdc13 SUMOylation peaks in early-mid S phase, prior to its known Cdk1-mediated phosphorylation, and the two modifications act antagonistically, suggesting that the opposite roles of Cdc13 in telomerase regulation can be separated temporally and regulated by distinct modifications.

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    • "However , c. 200 gene deletions (among them the well-characterized rad52D mutant) accelerated entry into senescence, and such cells often could not recover growth. A smaller number of strains (among them rif1D) accelerated both entry into senescence and subsequent recovery (Chang et al., 2011). A screen for enhancers of the MMS sensitivity of tel1D uncovered a small number (13) of genes. "
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    • "Siz1- and/or Siz2-dependent SUMOylation on Lys909 located in the C-terminus of Cdc13 promotes its interaction with Stn1 and formation of the CST complex. This modification peaks in early to mid S-phase (Hang et al., 2011). Cyclin-dependent kinase Cdk1 (Cdc28) phosphorylates Cdk1 on Thr308 located in the telomerase recruitment domain of Cdc13 Li et al., 2009). "
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    ABSTRACT: Telomere elongation by telomerase involves sequential steps that must be highly coordinated to ensure the maintenance of telomeres at a proper length. Telomerase is delivered to telomere ends, where it engages single-strand DNA end as a primer, elongates it, and dissociates from the telomeres via mechanism that is likely coupled to the synthesis of the complementary C-strand. In , the telomeric G-overhang bound Cdc13 acts as a platform for the recruitment of several factors that orchestrate timely transitions between these steps. In this review, we focus on some unresolved aspects of telomerase recruitment and on the mechanisms that regulate telomere elongation by telomerase after its recruitment to chromosome ends. We also highlight the key regulatory modifications of Cdc13 that promote transitions between the steps of telomere elongation.
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