MISCELLANEA Susan M. Gasser Swiss Institute for Experimental Cancer Research (ISREC), Chemin des Boveresses 155, CH-1066 Epalingesl Lausanne, Switzerland. 408 Telomeres, the means to many ends Telomeres edited by Elizabeth H. Blackburn and Carol M. Greider, Cold Spring Harbor Laboratory Press, 1995. $80.00 (396 pages) ISBN 0 87969 457 2 With the advent of the 1990s telo- meres have ceased to be an island unto themselves. No longer simply the termini of eukaryotic chromo- somes in need of a cap, telomeres have become preferred systems for the study of an ever-increasing num- ber of biological questions. Telomere research addresses questions about genetic stability, transcriptional regu- lation, ribozymes and RNA-containing enzymes, controls over DNA repli- cation, cellular transformation, senes- cence and differentiation, and explores nuclear organization. Many of these exciting new directions are presented in a CSH monograph entitled Telomeres. This book hails the coming of age of telomere research and should interest scientists from every field of biology. By covering oncology to structural studies, devel- opmental biology and enzymology, these chapters present insights on many key questions confronting the modern molecular biologist. While much of the book provides interesting reading, a few chapters are outstanding and deserve special note. Among these is Joe Gall’s historical account of telomere research, which serves as a prologue to the chapters that follow. Unlike many problems in modern cell biology that became de- fined only after the relevant molecules were identified, telomeres fascinated biologists long before they were known to be the only ‘free’ ends of DNA in the nucleus. The study of telomere positioning started with Rabl’s 19th- century description of looping chromo- somes, and telomere function became defined through Barbara McClintock’s insightful study on the fate of broken chromosomes in maize. The name ‘telo- mere’ and its description as a stabiliz- ing ‘cap’ for the chromosomal end surfaced first in 1938 as a result of Hermann Muller’s studies of X-ray- induced rearrangements in Drosophila 0 1996 Elsevier Science Ltd chromosomes’. The tradition of follow- ing telomeres as markers for chromo- some behaviour continues even today, and the combination of in situ hybrid- ization, immunofluorescence and im- proved microscopic techniques now allows scientists to pose sophisticated questions about meiotic chromosomal movement and interphase chromo- somal organization (Fig. 1). The sim- ple telomeric repeat, the more mys- terious subtelomeric elements, and ligands of both domains, are likely to play important roles in these dynamics. Another excellent contribution ,is Carol Creider’s chapter on telomerase, a unique class of DNA polymerase that carries along an RNA template as an integral part of the RNA-protein com- plex that maintains telomere length. The attention that telomerase has cap- tured is all the more impressive when one considers that the protein moiety of this enzyme remains virtually unex- plored. Indeed, Carol Greider’s chap- ter ends with the remarkable obser- vation that the recently cloned subunits of Tetrahymena telomerase are unre- lated to any protein in the database, despite the fact that remarkably con- served motifs (TT*/cCGC), are found on telomeres in ciliates, slime moulds and most vertebrates, including man. The necessity of a coordinated co- evolution for the telomerase RNA tem- plate, the protein components and the repeat itself, leads inevitably to thoughts of retrotransposons and reverse transcriptase as a model for this process. Mary Lou Pardue points out in her chapter that Drosophila appears to have solved the telomere-capping problem without the standard termi- nal TG-rich repeat sequence. Flies sta- bilize their chromosomal ends through RNA-mediated transpositions of large, middle repetitive elements that may not be unrelated to the subtelomeric repeats found in many other organ- isms. In yeast, the repetitive X and Y elements found in subtelomeric regions maintain high sequence homogeneity by recombination, rather than through an RNA intermediate. Nonetheless, it is an intriguing thought that these el- ements, like the fly He-T-A and TART retroposons, were once ‘invaders’ of the nucleus that have been captured and put to use to maintain chromo- some stability. The chapter on telomere proteins by Fang and Cech is beautifully written and synthesizes results from many species into clear insights about the kinds of proteins that bind and organ- ize this important chromosomal do- main. It is unfortunate that the se- quence of the human telomere repeat binding factor (TRFl) was published just shortly after the release of this monograph2. Intriguingly, TRFI, the related TTAGGG-binding factor from yeast (TBF1)3, and another human TTAGGG-binding factor all contain a single, related Myb-like DNA-binding domain, for which the name ‘telobox’ has been proposed4. The crystal struc- ture of the yeast telomere repeat binding protein, Repressor activator FIGURE 1 In situ hybridization with subtelomeric probes reveals a localization with Silent information regulatory (Sir) proteins in subnuclear foci. The wild-type diploid yeast strain was subjected to immunofluorescence with antibodies specific for either Silent information regulatory proteins 3 or 4, and these were reacted with a Texas-Red- conjugated secondary antibody. Cells were hybridized subsequently with a digoxidenin- dUTP-labelled Y’ subtelomeric probe detected by a fluorescein-conjugated anti-DIG F(ab) fragment. (a) Shows the merge of the Sir3 staining (red) and the Y’ probe (green); (b) shows the merge of the Sir4 staining (red) and the Y’ probe (green). Coincidence of the two signals above a certain threshold is shown in white. The figure shows a clustering of the 64 telomeres in this cell into a limited number of foci where proteins that influence telomere-proximal gene expression also colocalize. Quantitation shows that a majority of foci coincide. Image courtesy of T. Laroche, M. Cotta and S. Gasser. Arrowheads indicate colocalization of Sir proteins and subtelomeric repeat DNA; Bar, 1 Frn. trends in CELL BIOLOGY (Vol. 6) October 1996