Subtelomeric proteins negatively regulate telomere elongation in budding yeast

Berthiau, Anne-Sophie; Yankulov, Krassimir; Bah, Amadou; Revardel, Emmanuelle; Luciano, Pierre; Wellinger, Raymund J.; Géli, Vincent; Gilson, Éric

doi:10.1038/sj.emboj.7600975

Cited by 59 publications

(83 citation statements)

References 68 publications

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“…Indeed, even telomeres composed entirely of vertebrate-type repeats are kept stable during mitotic growth (18,20,21). Remarkably, on these telomeres, the hallmark telomere binding protein Rap1p appears to be replaced with Tbf1p, and there is some evidence to show that this latter protein can maintain a telomere length regulatory mechanism (19,20). However, it remained unclear how this mechanism could ensure telomere capping and stability in this situation.…”

Section: Discussionmentioning

confidence: 99%

“…It remains unclear whether in the situation of ScVSc telomeres, the vertebrate-type repeats, via the binding of Tbf1p, do actively contribute to overall telomere length regulation. Tbf1p has been shown to be able to contribute to telomere length regulation (19) and to promote telomere elongation of short telomeres, at least in the absence of Tel1p (42). However, it is also possible that the ϳ75-to 145-bp vertebrate repeats are too short to separate the proximal repeats from the distal repeat tracts to allow the establishment of a new and distally located independent telomere (43).…”

Section: Discussionmentioning

confidence: 99%

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Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Bah

Gilson

Wellinger

2011

Journal of Biological Chemistry

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Telomeres containing vertebrate-type DNA repeats can be stably maintained in Saccharomyces cerevisiae cells. We show here that telomerase is required for growth of yeast cells containing these vertebrate-type telomeres. When present at the chromosome termini, these heterologous repeats elicit a DNA damage response and a certain deprotection of telomeres. The data also show that these phenotypes are due only to the terminal localization of the vertebrate repeats because if they are sandwiched between native yeast repeats, no phenotype is observed. Indeed and quite surprisingly, in this latter situation, telomeres are of virtually normal lengths, despite the presence of up to 50% of heterologous repeats. Furthermore, the presence of the distal vertebrate-type repeats can cause increased problems of the replication fork. These results show that in budding yeast the integrity of the 3 overhang is required for proper termination of telomere replication as well as protection.Specialized ribonucleoprotein complexes known as telomeres protect the natural ends of eukaryotic chromosomes. In the budding yeast Saccharomyces cerevisiae, telomeres are composed of an ϳ300-bp double-stranded (ds) 4 tract of irregular repeats, abbreviated TG 1-3 /C 1-3 A, and terminate with a 12-to 14-nt single-stranded (ss) 3Ј overhang made of the TG 1-3 motifs (1-3). In contrast, vertebrate telomeres contain a ds tract containing thousands of T 2 AG 3 /C 3 TA 2 repeats and terminate with a ss 3Ј overhang made of T 2 AG 3 motifs (2, 4, 5).The complete replication of linear eukaryotic chromosomes requires the de novo addition of telomeric repeats to chromosome ends by telomerase, a specialized reverse transcriptase (for reviews, see Refs. 6 -9). The core telomerase components are a reverse-transcriptase catalytic subunit and a RNA moiety. In yeast, these components are known as Est2p and TLC1, respectively (8). The telomerase RNA always contains a short region that is complementary to the G-rich strand of telomeric repeats, and that region is used as a template for repeat addition (7, 9).Telomerase invalidation leads to gradual telomere shortening and ultimately causes cells to stop dividing (7, 9, 10). Nevertheless, cellular backup mechanisms can maintain telomeres in the absence of telomerase and ultimately preserve genome integrity. In this mode of telomere maintenance, which is known as alternative lengthening of telomeres in human cells, and survivor mode in Saccharomyces cerevisiae, telomeric DNA is maintained via homologous recombination-based mechanisms (11,12).By differentiating chromosomal ends from internal ds breaks, telomeres also prevent chromosomal ends from eliciting DNA damage checkpoint activation and protect telomeres from inappropriate DNA repair activity. Binding of the multiprotein complex shelterin is essential for both protecting and maintaining the length of mammalian telomeres (13,14). Rap1p, one of the several proteins associated with similar functions at budding yeast telomeres, binds directly to ds telomeric repeats ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Bah

Gilson

Wellinger

2011

Journal of Biological Chemistry

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“…For instance in S. cerevisiae, a function-unknown protein, Cue2 protein (accession number is NP_012833), has the Smr domain in its C-terminal region. A genome-wide study (51) has shown that Cue2 protein interacts with a subtelomeric protein, Tbf1, which negatively regulates telomerase-dependent elongation of the telomere (52). Although the mechanism underlying this regulation has been unknown, the branched-structure preference of the Smr endonuclease domain may be a clue for understanding it, because the telomere contains the branched DNA structures (53).…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of MutS2 Endonuclease Domain and the Mechanism of Homologous Recombination Suppression

Fukui

Nakagawa

Kitamura

et al. 2008

Journal of Biological Chemistry

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DNA recombination events need to be strictly regulated, because an increase in the recombinational frequency causes unfavorable alteration of genetic information. Recent studies revealed the existence of a novel anti-recombination enzyme, MutS2. However, the mechanism by which MutS2 inhibits homologous recombination has been unknown. Previously, we found that Thermus thermophilus MutS2 (ttMutS2) harbors an endonuclease activity and that this activity is confined to the C-terminal domain, whose amino acid sequence is widely conserved in a variety of proteins with unknown function from almost all organisms ranging from bacteria to man. In this study, we determined the crystal structure of the ttMutS2 endonuclease domain at 1.7-Å resolution, which resembles the structure of the DNase I-like catalytic domain of Escherichia coli RNase E, a sequence-nonspecific endonuclease. The N-terminal domain of ttMutS2, however, recognized branched DNA structures, including the Holliday junction and D-loop structure, a primary intermediate in homologous recombination. The full-length of ttMutS2 digested the branched DNA structures at the junction. These results indicate that ttMutS2 suppresses homologous recombination through a novel mechanism involving resolution of early intermediates.Homologous recombination is required for a variety of DNA transactions such as DNA repair, the rescue of stalled replication forks, and the creation of genetic diversity (1-4). The reaction begins with the introduction of a double strand break in the homologous region of the donor strand (5-7). The ends of the strand are resected by exonucleases to generate termini with 3Ј-overhangs. Then, RecA protein (Rad51 in eukaryotes) recognizes the single-stranded region of the DNA and catalyzes the invasion into the target double-stranded DNA to generate the D-loop structure. The sequential DNA synthesis and ligation yield a general intermediate called the Holliday junction. Several junction-specific endonucleases resolve the junction, and DNA ligase reseals the nicks to complete the process of homologous recombination. This homologous recombination process is utilized not only for the recovery but also for the alteration of genetic information.To avoid unfavorable alteration of genetic information, organisms are equipped with a series of enzymes that not only promote but also suppress homologous recombination (4). Recent studies have shown that bacterial and plant MutS2 proteins are candidate anti-recombination enzymes (8, 9). MutS2 is a paralogue of Escherichia coli MutS, which recognizes a mismatched base pair and induces the mismatch repair (MMR) 2 pathway (Fig. 1). Proteins homologous to E. coli MutS are widely distributed and classified into two subfamilies, MutSI and MutSII, on the basis of amino acid sequence comparison (10). The former is responsible for MMR and includes bacterial MutS and eukaryotic MSH2, MSH3, and MSH6 (11-12). The latter, MutSII, is expected to not be involved in MMR but in recombinational events, and includes bacterial MutS2 a...

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“…In budding yeast, deregulation of telomere size, stability and function is observed in rap1 mutants (Kyrion et al, 1993) and Rap1-Sir4 interactions play an important role in initiating the assembly of heterochromatin (Luo et al, 2002). Similarly, subtelomere proteins have been shown to negatively regulate telomere elongation (Berthiau et al, 2006), and SIR3 and SIR4 are required for the integrity of telomeres in budding yeast (Palladino et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Role of heterochromatin in suppressing subtelomeric recombination in fission yeast

Bisht

Arora

Ahmed

et al. 2008

Yeast

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Telomere length is regulated by a complex interplay of several factors, including telomerase, telomere-binding proteins, DNA replication machinery and recombination. In yeast, DNA polymerase α is required for de novo synthesis of telomeres from broken ends of DNA, and it also suppresses the elongation of normal telomeric repeats. Heterochromatin proteins Clr1-Clr4 and Swi6 and DNA polα organize heterochromatin structure at mating type, centromere, rDNA and telomere regions that are refractory to transcription and recombination in Schizosaccharomyces pombe. Here, we have addressed the role of heterochromatin structure in regulating the integrity and organization of telomeric regions. Here, we show that subtelomeric duplication and rearrangements occur in polα and heterochromatin mutants and find that some of the putative duplication events are dependent on the Rad50 pathway. Thus, our study shows a role of heterochromatin in maintaining the integrity of the subtelomeric regions by suppressing their recombination in Sz. pombe.

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Subtelomeric proteins negatively regulate telomere elongation in budding yeast

Cited by 59 publications

References 68 publications

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Crystal Structure of MutS2 Endonuclease Domain and the Mechanism of Homologous Recombination Suppression

Role of heterochromatin in suppressing subtelomeric recombination in fission yeast

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