Telomeres: Structures in need of unwinding

Paeschke, Katrin; McDonald, Karin R.; Zakian, Virginia A.

doi:10.1016/j.febslet.2010.07.007

Cited by 85 publications

(71 citation statements)

References 210 publications

(297 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, incomplete lagging strand synthesis is expected to lead to rapid telomereshortening events in subsequent rounds of DNA replication if gapped C strands serve as replication templates. In addition, telomeric G-rich ssDNA can fold into G-quadruplex structures that impede DNA replication and may cause telomere-shortening events (Paeschke et al 2010;Vannier et al 2012). Consistent with this notion, we observed accumulation of telomere-free ends in cells that expressed mutant CTC1 (V259M).…”

Section: Discussionsupporting

confidence: 84%

Molecular basis of telomere syndrome caused by CTC1 mutations

2013

View full text Add to dashboard Cite

Mutations in CTC1 lead to the telomere syndromes Coats Plus and dyskeratosis congenita (DC), but the molecular mechanisms involved remain unknown. CTC1 forms with STN1 and TEN1 a trimeric complex termed CST, which binds ssDNA, promotes telomere DNA synthesis, and inhibits telomerase-mediated telomere elongation. Here we identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase a-primase (pola-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo. While having diverse molecular defects, CTC1 mutations commonly lead to the accumulation of internal single-stranded gaps of telomeric DNA, suggesting telomere DNA replication defects as a primary cause of the disease. Strikingly, mutations in CTC1 may also unleash telomerase repression and telomere length control. Hence, the telomere defect initiated by CTC1 mutations is distinct from the telomerase insufficiencies seen in classical forms of telomere syndromes, which cause short telomeres due to reduced maintenance of distal telomeric ends by telomerase. Our analysis provides molecular evidence that CST collaborates with DNA pola-primase to promote faithful telomere DNA replication.

show abstract

Section: Discussionsupporting

confidence: 84%

Molecular basis of telomere syndrome caused by CTC1 mutations

2013

View full text Add to dashboard Cite

show abstract

“…It has been proposed that in the absence of Sae2 and Sgs1, the Ku complex prevents the processing of replication-born DSBs and hence their repair by HR 36 . Telomeres are a challenge for the replication machinery 29 rising the possibility of an increased occurrence of fork arrest and associated damage in the absence of Sae2 and Sgs1. We used neutral/neutral two-dimensional gel electrophoresis (2DGE) followed by Southern blotting to directly observe telomere replication intermediates in sae2D sgs1D double mutant cells grown for about 30 PDs, before telomeres abruptly shorten.…”

Section: Resultsmentioning

confidence: 99%

“…The MRX complex also plays a key role in targeting telomerase to short telomeres 26 by recruiting Tel1 via specific interaction with a conserved motif in the Xrs2 C-terminus [26][27][28] . Finally, owing to a high GC content and the presence of stable protein/DNA complexes, telomeres are a challenge for the replication machinery that might become dependent on a specific set of proteins to avoid fork collapse in telomeric repeats 6,29 .…”

mentioning

confidence: 99%

Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

et al. 2014

View full text Add to dashboard Cite

In budding yeast, DNA ends are processed by the consecutive action of MRX/Sae2 and two redundant pathways dependent on Sgs1/Dna2 and Exo1, and this processing is counteracted by Ku heterodimer. Here we show that DNA end resection by Sae2 and Sgs1 is dispensable for normal telomere maintenance by telomerase. Instead, these proteins facilitate telomere replication and limit the accumulation of single-strand DNA (ssDNA) at replication fork pause sites. Loss of Sae2 and Sgs1 drives selection for compensatory mutations, notably in Ku, which are responsible for abrupt telomere shortening in cells lacking Sae2 and Sgs1. In telomerase-negative cells, Sae2 and Sgs1 play non-overlapping roles in generating ssDNA at eroded telomeres and are required for the formation of type II survivors. Thus, although their primary function in telomerase-positive cells is to sustain DNA replication over the sites that are prone to fork pausing, Sae2 and Sgs1 contribute to telomere resection in telomerase-deficient cells.

show abstract

“…Recent evidence obtained in a variety of systems, including budding yeast, fission yeast, and mammalian cells, strongly suggests that the passage of the replication fork through telomeric repeats is a challenge and requires the presence of telomere repeat binding proteins and specialized helicases (45)(46)(47)(48). It has been proposed that these characteristics have important ramifications for human chromosome stability during DNA replication and for integration of mobile DNA elements (46).…”

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

View full text Add to dashboard Cite

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 ...

show abstract

Telomeres: Structures in need of unwinding

Cited by 85 publications

References 210 publications

Molecular basis of telomere syndrome caused by CTC1 mutations

Molecular basis of telomere syndrome caused by CTC1 mutations

Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

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

Contact Info

Product

Resources

About