scholarly journals Control of Telomeric DNA Replication: Genetics, Molecular Biology, and Physiology

Author(s):  
Akira Matsuura ◽  
Aiko Matsui
2001 ◽  
Vol 114 (10) ◽  
pp. 1798-1799
Author(s):  
S.K. Evans ◽  
V. Lundblad

The Yeast Nucleus edited by P. Fantes and J. Beggs Oxford University Press (2000) 338 pages. ISBN 0–19-963772-5?32.50 Without question, numerous studies in yeast and mammals have revealed a striking commonality of underlying mechanisms that govern basic biological operations. Perhaps the most famous example from recent years has been the recognition that genes required for maintaining the yeast genome play a critical role in preventing cancer in humans. However, examining the molecular differences - the variations on a common theme, so to speak - can also be useful for understanding core biological processes. These ideas are the foundation for The Yeast Nucleus, a valuable contribution to Oxford University Press's ‘Frontiers in Molecular Biology’ series. The textbook compares and contrasts various nuclear processes in budding yeast (Saccharomyces cerevisiae) and fission yeast (Schizosaccharomyces pombe), pointing out the similarities - and differences - that make these two somewhat unrelated yeasts the dominant model systems for studying fundamental eukaryotic processes. Each of the nine chapters is an authoritative review written by experts in the field. The opening chapter surveys the technologies that have propelled efforts to elucidate the functions of the ~6000 predicted protein-encoding genes in S. cerevisiae; this chapter includes sections on bioinformatics, genome-wide transcription and proteome analysis. The next four chapters - covering DNA replication, the mitotic cell cycle, cell cycle checkpoints and nuclear division - form a well-integrated quartet that describes the complex molecular and genetic pathways governing faithful chromosome replication and segregation. The cell cycle chapter, in particular, is presented from a unique perspective: rather than focusing on the physiological changes that occur at each stage, it instead illustrates the molecular machines (i.e. the cyclin-dependent kinases) that propel the cell cycle. The fifth chapter provides a comprehensive discussion on RNA polymerase II transcription in S. cerevisiae that incorporates sections on general transcription factors, coactivators and repressors. It also includes a brief synopsis of the effects of chromatin on transcription, which creates a nice segue to the following chapter on the structure of chromatin at centromeres and telomeres. The final two chapters, on pre-mRNA splicing and nuclear transport of RNA and proteins, focus mainly on the mechanisms identified in budding yeast. The only obvious shortcoming with respect to the scope of this textbook is that it fails to include in-depth discussions of DNA repair and recombination. This publication has several attributes that make it an excellent reference source. First, it is a comprehensive review that weaves a great deal of supplementary information into each chapter. It not only is extensively referenced, but also frequently includes citations to reviews and to yeast database websites for further details. Second, the book is well written and readable. Each chapter is organized in a logical sequence - for example, the chapter on DNA replication starts with origin recognition and ends with Okazaki fragment processing. Furthermore, although the descriptions of genetic and molecular pathways are often encyclopedic, extensive summary tables and/or simple diagrams supplement the discussions and assist the reader in grasping the information. The value of such summary tables can be greatly appreciated when navigating through the maelstrom of mismatched S. cerevisiae and S. pombe CDC and RAD gene nomenclature. Lastly, there is an overall congruity that pulls together the topics of the separate chapters and relates them to one another. For instance, examples of genome-wide analyses are highlighted in several chapters to convey the practicality and usefulness of this approach, and the chapters on splicing and nuclear transport both include small sections that link these activities to other nuclear processes that have been discussed. It is important to note, however, that a complete understanding of many of the sections will require prior knowledge of fundamental genetic principles and molecular biology techniques; for this reason, the book may be better suited to the more advanced reader. The Yeast Nucleus is designed to stimulate thinking - not only about the similarities and differences between the budding and fission yeasts, but about whether comparable mechanisms might be used in other organisms as well. To achieve this goal, it goes beyond a comparative analysis of the two yeasts, and draws parallels with bacteriophage, viral and a variety of metazoan systems when applicable. The result is a well-integrated view that succeeds in providing a foundation for provoking thought about the unity of basic biological mechanisms. Moreover, each chapter concludes with an insightful look at the future direction of the field. In these regards, this publication will serve as a fabulous guidebook for experts as well as students.


Author(s):  
Erin Bonnell ◽  
Emeline Pasquier ◽  
Raymund J. Wellinger

Eukaryotic genomes are highly complex and divided into linear chromosomes that require end protection from unwarranted fusions, recombination, and degradation in order to maintain genomic stability. This is accomplished through the conserved specialized nucleoprotein structure of telomeres. Due to the repetitive nature of telomeric DNA, and the unusual terminal structure, namely a protruding single stranded 3′ DNA end, completing telomeric DNA replication in a timely and efficient manner is a challenge. For example, the end replication problem causes a progressive shortening of telomeric DNA at each round of DNA replication, thus telomeres eventually lose their protective capacity. This phenomenon is counteracted by the recruitment and the activation at telomeres of the specialized reverse transcriptase telomerase. Despite the importance of telomerase in providing a mechanism for complete replication of telomeric ends, the majority of telomere replication is in fact carried out by the conventional DNA replication machinery. There is significant evidence demonstrating that progression of replication forks is hampered at chromosomal ends due to telomeric sequences prone to form secondary structures, tightly DNA-bound proteins, and the heterochromatic nature of telomeres. The telomeric loop (t-loop) formed by invasion of the 3′-end into telomeric duplex sequences may also impede the passage of replication fork. Replication fork stalling can lead to fork collapse and DNA breaks, a major cause of genomic instability triggered notably by unwanted repair events. Moreover, at chromosomal ends, unreplicated DNA distal to a stalled fork cannot be rescued by a fork coming from the opposite direction. This highlights the importance of the multiple mechanisms involved in overcoming fork progression obstacles at telomeres. Consequently, numerous factors participate in efficient telomeric DNA duplication by preventing replication fork stalling or promoting the restart of a stalled replication fork at telomeres. In this review, we will discuss difficulties associated with the passage of the replication fork through telomeres in both fission and budding yeasts as well as mammals, highlighting conserved mechanisms implicated in maintaining telomere integrity during replication, thus preserving a stable genome.


2020 ◽  
Author(s):  
Margherita Paschini ◽  
Cynthia M. Reyes ◽  
Abigail E. Gillespie ◽  
Karen A. Lewis ◽  
Leslie W. Glustrom ◽  
...  

AbstractTelomeres present unique challenges for genomes with linear chromosomes, including the inability of the semi-conservative DNA replication machinery to fully duplicate the ends of linear molecules. This is solved in virtually all eukaryotes by the enzyme telomerase, through the addition of telomeric repeats onto chromosome ends. It is widely assumed that the primary site of action for telomerase is the single-stranded G-rich overhang at the ends of chromosomes, formed after DNA replication is complete. We show here that the preferred substrate for telomerase in wild type yeast is instead a collapsed fork generated during replication of duplex telomeric DNA. Furthermore, newly collapsed forks are extensively elongated by telomerase by as much as ∼200 nucleotides in a single cell division, indicating that a major source of newly synthesized telomeric repeats in wild type cells occurs at collapsed forks. Fork collapse and the subsequent response by telomerase are coordinated by the dual activities of a telomere-dedicated RPA-like complex, which facilitates replication of duplex telomeric DNA and also recruits telomerase to the fork, thereby ensuring a high probability of re-elongation if DNA replication fails. We further show that the ability of telomerase to elongate newly collapsed forks is dependent on the Rad51 protein, indicating that telomerase activity in response to fork collapse proceeds through a regulatory pathway distinct from how telomerase engages fully replicated chromosome termini. We propose a new model in which spontaneous replication fork collapse and the subsequent response by telomerase is a major determinant of telomere length homeostasis.


2020 ◽  
Vol 82 (1) ◽  
pp. 49-51
Author(s):  
Ladislav Merta ◽  
Tomáš Pinkr ◽  
Vanda Janštová

Molecular biology topics tend to be abstract and hard to visualize, and consequently pupils form many misconceptions about genetics and molecular biology. We describe how to make a hands-on educational set that provides visual and tactile modeling of DNA replication, transcription, polymerase chain reaction (PCR), and random mutations so that students can examine these processes in detail. The set is inexpensive and easy to make, has been used successfully, and allows for modification to fit individual teachers' needs.


2005 ◽  
Vol 25 (7) ◽  
pp. 2708-2721 ◽  
Author(s):  
Wei-Qin Jiang ◽  
Ze-Huai Zhong ◽  
Jeremy D. Henson ◽  
Axel A. Neumann ◽  
Andy C.-M. Chang ◽  
...  

ABSTRACT Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in telomere binding, DNA replication, and recombination. The ALT mechanism appears to involve recombination-mediated DNA replication, but the molecular details are largely unknown. In telomerase-null Saccharomyces cerevisiae, an analogous survivor mechanism is dependent on the RAD50 gene. We demonstrate here that overexpression of Sp100, a constituent of promyelocytic leukemia nuclear bodies, sequestered the MRE11, RAD50, and NBS1 recombination proteins away from APBs. This resulted in repression of the ALT mechanism, as evidenced by progressive telomere shortening at 121 bp per population doubling, a rate within the range found in telomerase-negative normal cells, suppression of rapid telomere length changes, and suppression of APB formation. Spontaneously generated C-terminally truncated Sp100 that did not sequester the MRE11, RAD50, and NBS1 proteins failed to inhibit ALT. These findings identify for the first time proteins that are required for the ALT mechanism.


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