HIGHLIGHTS

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | JUNE 2004 | 419

HIGHLIGHT ADVISORS

UELI AEBI

UNIVERSITY OF BASEL,SWITZERLAND

TOM L. BLUNDELL

UNIVERSITY OF CAMBRIDGE, UK

JOAN S. BRUGGE

HARVARD MEDICAL SCHOOL,BOSTON, MA, USA

PASCALE COSSART

INSTITUT PASTEUR, PARIS,FRANCE

PAMELA GANNON

CELL AND MOLECULARBIOLOGY ONLINE

SUSAN M. GASSER

UNIVERSITY OF GENEVA,SWITZERLAND

JEAN GRUENBERG

UNIVERSITY OF GENEVA,SWITZERLAND

ULRICH HARTL

MAX-PLANCK-INSTITUTE,MARTINSRIED, GERMANY

STEPHEN P. JACKSON

WELLCOME/CRC INSTITUTE,CAMBRIDGE, UK

WALTER NEUPERT

MUNICH UNIVERSITY, GERMANY

TONY PAWSON

SAMUEL LUNENFELD RESEARCHINSTITUTE, TORONTO, CANADA

NORBERT PERRIMON

HARVARD MEDICAL SCHOOL,BOSTON, MA, USA

THOMAS D. POLLARD

YALE UNIVERSITY, NEW HAVEN, CT, USA

JOHN C. REED

THE BURNHAM INSTITUTE, LA JOLLA, CA, USA

ANNE RIDLEY

LUDWIG INSTITUTE FOR CANCERRESEARCH, LONDON, UK

KAREN VOUSDEN

BEATSON INSTITUTE FOR CANCER RESEARCH, GLASGOW, UK

Is telomere-length control a matter ofelongation efficiency, with the telom-erase enzyme being recruited to alltelomeres but having increased activ-ity on shorter telomeres? Or doestelomerase act on a subset of telom-eres, its recruitment being dependenton telomere length? In Cell, JoachimLingner and colleagues now provideevidence for the latter model.

To study the mechanisms oftelomere-length homeostasis,Lingner and colleagues developed asystem for measuring single telom-ere-elongation events in vivo. Theyused a Saccharomyces cerevisiae strainthat was deficient for telomerase andreintroduced the enzyme by matingwith a wild-type strain. Telomeresfrom the original telomerase-negativestrain were then amplified by PCR,cloned and sequenced. Yeast telom-erase produces irregular telomericDNA sequences, which was sufficientto distinguish individual telomere-elongation events from each other.

By measuring telomere elongationover the course of a single cell cycle,the authors showed that within onecell cycle, less than 40% of telomereswere extended. This implies thattelomere-length homeostasis is notregulated by the enzymatic activity oftelomerase, as suggested by the firstmodel.

When Lingner and co-workerscompared the extent of telomereelongation with telomere length, theyfound that telomere extension lengthwas highly variable and independent

of their original telomere length. But,when they sorted telomeres accordingto their length and plotted the averagetelomere length against the frequencyof elongation, the correlation was sig-nificant. In fact, the shortest telom-eres were 6 times more likely to beelongated than the longer, wild-type-length telomeres.

So, how does telomere length reg-ulate the frequency of telomere elon-gation? It has been known for sometime that certain telomere-bindingproteins, such as Rap1 in S. cerevisiae,are involved in a negative-feedbackmechanism that regulates telomerelength. This so-called ‘protein-count-ing mechanism’ transmits informa-tion about the length of the telomereon the basis of the number of telom-ere-bound proteins. The Rif1 andRif2 proteins, which are recruited totelomeres by Rap1, are thought tomediate the Rap1-counting mecha-nism of telomere-length control.

The authors found that, in theabsence of either Rif1 or Rif2, the fre-quency of telomere elongation wasabout twofold higher compared withwild-type strains. So, they suggestedthat Rif1 and Rif2 promote thenonextendible telomeric state inwhich telomere elongation is some-how blocked.

Based on their findings, Lingnerand colleagues propose a binary-switch model in which long telomeresrecruit a lot of the Rap1–Rif1–Rif2complex, which causes the telomeresto switch to a nonextendible state.But, when telomeres get shorter andlose most of the complex, theybecome extendible. It is this equilib-rium between the two telomere statesthat maintains telomere length.

Arianne Heinrichs

References and linksORIGINAL RESEARCH PAPER Teixeira, M. T. et al.Telomere length homeostasis is achieved via aswitch between telomerase-extendible and -nonextendible states. Cell 117, 323–335 (2004)

The long andthe short of it

T E LO M E R E S

© 2004 Nature Publishing Group