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Getting to the end: telomerase access in yeast and humans

Nature Reviews Molecular Cell Biology volume 4, pages 948–959 (2003)Cite this article

Key Points

  • The ends of linear chromosomes are problematic for the eukaryotic DNA-replication machinery. Eukaryotes have evolved specialized structures at chromosome ends — known as telomeres — that are replicated by a unique mechanism using the reverse transcriptase, telomerase.

  • Telomeres are comprised of G-rich DNA repeats, the sequence of which varies among different organisms. Telomeres facilitate the complete replication of linear chromosomes and protect chromosome ends from degradation and end-to-end fusions.

  • In yeast and humans, the G-rich strand of telomeres extends in the 3′ direction to form a single-stranded G-tail. G-tails are telomerase substrates and bind single-strand-specific DNA-binding proteins that protect chromosome ends from degradation and from fusions with DNA breaks or other chromosome ends.

  • Telomerase action is highly regulated in vivo as inappropriate telomere addition is deleterious and can stabilize chromosomal aberrations.

  • Telomerase can be regulated in various ways: by modulating the telomeric chromatin structure through single-stranded or double-stranded telomeric-DNA-binding proteins and their associated factors; by using telomerase accessory factors; by dissociating active telomerase from chromosome ends; and by sequestering active telomerase in specific subcellular compartments, such as the nucleolus.

  • Free single-stranded DNA can signal to DNA-damage-response pathways; so, telomeric G-tails must be shielded to avoid detection as damaged DNA. Since telomeres do not fuse with each other or with DNA breaks, telomeres are also protected from non-homologous end joining. Surprisingly, proteins such as Ku and the Mre11 complex that are involved in non-homologous end joining and DNA checkpoints are important for telomere maintenance.

  • Many of the components involved in regulating access of telomerase to the telomere are conserved from yeast to humans.

Abstract

In organisms with linear chromosomes, telomeres are essential to maintain genome integrity. However, inappropriate telomere addition, for example to double-stranded DNA breaks, might stabilize deleterious genetic changes. Therefore, telomere addition by telomerase is highly regulated, for example by mechanisms that determine the accessibility of telomeres to elongation by telomerase. These mechanisms, which have been studied mainly in budding yeast and human cell culture, can be subdivided into two classes: mechanisms that modulate the telomeric chromatin structure and those that sequester active telomerase from chromosome ends.

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Figure 1: Telomerase-mediated telomere lengthening in yeast.
Figure 2: Telomere ends contain G-rich overhangs.
Figure 3: Sequestration of telomerase in the nucleolus.

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Acknowledgements

We thank T. Fisher and M. Sabourin for critical reading of the manuscript, S. Schnakenberg for help with the figures and B. Lenzmeier and J. Bessler for thoughtful discussions. Work in the Zakian lab is supported by grants from the National Institutes of Health (NIH). M.K.M. is supported by the Damon Runyon Cancer Research Foundation. L.R.V. was funded in part by the Helen Hay Whitney Foundation and by the NIH.

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  1. Leticia R. Vega and Maria K. Mateyak: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    Leticia R. Vega, Maria K. Mateyak & Virginia A. Zakian

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  1. Leticia R. Vega
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  2. Maria K. Mateyak
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  3. Virginia A. Zakian
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Correspondence to Virginia A. Zakian.

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DATABASES

LocusLink

hTR

Saccharomyces Genome Database

Cdc13

Est1

Est2

Est3

Ku80

Mec1

PIF1

Rap1

Rif1

Rif2

Sgs1

Stn1

Ten1

TLC1

Swiss-Prot

EST1A

Ku86

MRE11

NBS1

PINX1

RAD50

RAP1

tankyrase 1

tankyrase 2

TERT

TIN2

TRF1

TRF2

WRN

Glossary

TELOMERASE

Specialized ribonucleoprotein, the catalytic core of which is composed of an RNA subunit and a reverse transcriptase subunit that facilitates the replication of linear chromosome ends or telomeres. The RNA subunit contains the template for sequence addition (3′ CACACACCCACACCAC 5′ in S. cerevisiae and 3′ CAAUCCCAAUC 5′ in humans).

OKAZAKI FRAGMENT

Short DNA fragment that is formed during DNA replication due to the discontinuous synthesis of the lagging strand. Okazaki fragments are initiated with an 8–12-base stretch of RNA.

REVERSE TRANSCRIPTASE

An enzyme that copies single-stranded RNA into a single-stranded DNA.

T-LOOP

Duplex telomeric loop that results from invasion of 3′ G-rich overhangs into duplex telomeric regions. T-loops have been found on eukaryotic telomeres and range in size from 0.3 kb to >30 kb.

MYB-LIKE DOMAIN

Highly conserved DNA-binding domain that is composed of tandem repeats of a helix-turn-helix motif.

KU PROTEIN

A highly conserved heterodimer consisting of ∼70- and ∼80-kDa subunits that binds at double-stranded DNA breaks and at telomeres and is important for DNA repair and telomere functions.

ADENOSINE-DIPHOSPHATE-RIBOSE POLYMERASE

An enzyme that uses NAD+ as a substrate to produce peptidyl-glutamic acid poly-ADP-ribose-modified proteins. This modification regulates various processes such as differentiation, proliferation and the repair of single-stranded DNA breaks.

PROTEASOME

A multi-protein complex that degrades proteins marked for destruction by ubiquitylation.

UBIQUITYLATION

The addition of the small evolutionarily conserved polypeptide, ubiquitin, to proteins that are targeted for destruction.

HELICASE

An enzyme that uses the energy of ATP hydrolysis to unwind duplex nucleic acids

EXONUCLEASE

An enzyme that hydrolyzes ester linkages within nucleic acids. They can remove nucleotides from either the 3′ or 5′ end of the molecule.

MRE11 COMPLEX

A highly conserved protein complex that is composed of MRE11, RAD50 and NBS1 (in humans) and Mre11, Rad50 and Xrs2 (also known as the MRX complex, in yeast) and that is involved in detection, signalling and repair of DNA damage. In humans, mutations in ATM, MRE11 and NBS1 are associated with increased predisposition to cancer and cause ataxia–telangiectasia (AT), AT-like disorder (AT-LD) and Nijmegen breakage syndrome (NBS), respectively.

WRN HELICASE/EXONUCLEASE

WRN is a member of the RecQ helicase subfamily and has 3′→5′ helicase and 3′→5′ exonuclease activities. Mutations in human WRN result in Werner syndrome, an autosomal-recessive disease that is characterized by premature ageing, chromosome instability and telomere–telomere fusions.

NON-HOMOLOGOUS END JOINING

(NHEJ). A double-stranded DNA break (DSB) repair pathway that involves the largely homology-independent ligation of two DNA ends.

INTRA-S-PHASE CHECKPOINT

Pathway that responds to stalled replication forks and other DNA damage during S phase by activating the ATM-like kinases Mec1 and Rad53. Checkpoint activation results in delayed S-phase progression and inhibits spindle elongation.

SMALL NUCLEOLAR RNA

(snoRNA). Stable RNA species in the eukaryotic nucleolus, most of which function to target the major nucleotide modifications in ribosomal RNA or are involved in rRNA processing. There are three classes of snoRNAs: box H/ACA snoRNAs, box C/D snoRNAs and 7-2/MRP snoRNAs.

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Vega, L., Mateyak, M. & Zakian, V. Getting to the end: telomerase access in yeast and humans. Nat Rev Mol Cell Biol 4, 948–959 (2003). https://doi.org/10.1038/nrm1256

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