SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1 ^Tpp1 to modulate shelterin–Stn1 interaction in fission yeast

Abstract

Telomeres protect DNA ends of linear eukaryotic chromosomes from degradation and fusion, and ensure complete replication of the terminal DNA through recruitment of telomerase. The regulation of telomerase is a critical area of telomere research and includes cis regulation by the shelterin complex in mammals and fission yeast. We have identified a key component of this regulatory pathway as the SUMOylation [the covalent attachment of a small ubiquitin-like modifier (SUMO) to target proteins] of a shelterin subunit in fission yeast. SUMOylation is known to be involved in the negative regulation of telomere extension by telomerase; however, how SUMOylation limits the action of telomerase was unknown until now. We show that SUMOylation of the shelterin subunit TPP1 homolog in Schizosaccharomyces pombe (Tpz1) on lysine 242 is important for telomere length homeostasis. Furthermore, we establish that Tpz1 SUMOylation prevents telomerase accumulation at telomeres by promoting recruitment of Stn1-Ten1 to telomeres. Our findings provide major mechanistic insights into how the SUMOylation pathway collaborates with shelterin and Stn1-Ten1 complexes to regulate telomere length.CST complex | DNA replication | S-phase | cell cycle T elomeres protect DNA ends of linear eukaryotic chromosomes from degradation and fusion, and ensure replication of the terminal DNA (1, 2). In most eukaryotes, telomere length is maintained predominantly by telomerase, a specialized reverse transcriptase that adds telomeric DNA to the 3′ ends of chromosomes. In addition, a DNA homologous recombination (HR)-dependent mechanism, known as the alternative lengthening of telomeres (ALT) pathway, may contribute to telomere maintenance (3). Given the significant contribution of dysfunctional telomeres to genome instability, cancer development, and aging (4), understanding how telomere maintenance and the cellular response to telomere dysfunction is important. Maintenance of stable telomere length requires a balance of positive and negative regulators of telomerase. The molecular details of such regulation are not completely understood, however, and further investigation of how telomeres ensure genomic integrity is needed.Telomere regulation is largely mediated by the shelterin complex specifically bound to telomeric repeats (2). In mammalian cells, the shelterin complex (composed of TRF1, TRF2, RAP1, TIN2, TPP1, and POT1) plays critical roles in (i) regulating telomerase recruitment, (ii) preventing full-scale activation of DNA damage checkpoint responses by checkpoint kinases ATM and ATR, (iii) preventing DNA resection, and (iv) preventing telomere rearrangement and fusion by HR, classical nonhomologous end-joining (NHEJ), or alternative NHEJ (2, 5, 6).Fission yeast Schizosaccharomyces pombe serves as an attractive model system for studying telomere regulation, because it uses a complex that closely resembles the mammalian shelterin (7). Fission yeast shelterin is composed of Taz1 (an ortholog of TRF1 and TRF2), Rap1, Poz1 (a possible analog of TIN2), TPP...

SUMO-targeted ubiquitin ligase activity can either suppress or promote genome instability, depending on the nature of the DNA lesion

“…Therefore, deletion of Pli1 causes telomere elongation, which can be readily visualized by Southern analysis of chromosome termini (Fig 6A, [14, 18–20]). Interestingly, in addition to the expected telomere elongation in pli1Δ cells, our Southern analyses indicated telomere homeostasis defects in some other SUMO pathway mutants (Fig 6A), which we analyzed further.…”

Pli1PIAS1 SUMO Ligase Protected by the Nuclear Pore-associated SUMO Protease Ulp1SENP1/2

“…Notably, like centromeres, telomeres are also clustered at the nuclear periphery and are subject to Pli1-dependent regulation (40,41). Pli1 sumoylates the telomere protein Tpz1 to support a mechanism for inhibiting excessive telomerase activity at chromosome ends (57). Therefore, based on the synonymous centromere silencing roles of Pli1 and Nup132, we envisage that Tpz1 will be hyposumoylated in cells lacking Nup132, leading to telomere elongation.…”

Dynamic Interactions of Arabidopsis TEN1: Stabilizing Telomeres in Response to Heat Stress

“…Telomere length homeostasis is achieved by a highly orchestrated, but poorly understood, series of conformational changes that sequentially convert the G-overhang into telomerase-extendable and nonextendable states (Blackburn, 2001;Teixeira et al, 2004). This binary switch is controlled by longrange protein interactions (Loayza and De Lange, 2003;Marcand et al, 1997), dynamic shifts among core components of telomere complexes (Jun et al, 2013), and posttranslational modification (Garg et al, 2014;Liu et al, 2014;Miyagawa et al, 2014;Zhang et al, 2013).…”