Telomeres and meiosis in health and disease

Telomeres are important segments of chromosomes that protect chromosome ends from nucleolytic degradation and fusion. At meiosis telomeres display an unprecedented behavior which involves their attachment and motility along the nuclear envelope. The movements become restricted to a limited nuclear sector during the so-called bouquet stage, which is widely conserved among species. Recent observations suggest that telomere clustering involves actin and/or microtubules, and is altered in the presence of impaired recombinogenic and chromosome related functions. This review aims to provide an overview of what is currently known about meiotic telomere attachment, dynamics and regulation in synaptic meiosis.     

Telomeres and meiosis in health and disease

Telomeres are important segments of chromosomes that protect chromosome ends from nucleolytic degradation and fusion. At meiosis telomeres display an unprecedented behavior which involves their attachment and motility along the nuclear envelope. The movements become restricted to a limited nuclear sector during the so-called bouquet stage, which is widely conserved among species. Recent observations suggest that telomere clustering involves actin and/or microtubules, and is altered in the presence of impaired recombinogenic and chromosome related functions. This review aims to provide an overview of what is currently known about meiotic telomere attachment, dynamics and regulation in synaptic meiosis.     

Gathering up meiotic telomeres: a novel function of the microtubule-organizing center

During meiosis, telomeres cluster and promote homologous chromosome pairing. Telomere clustering depends on conserved SUN and KASH domain nuclear membrane proteins, which form a complex called the linker of nucleoskeleton and cytoskeleton (LINC) and connect telomeres with the cytoskeleton. It has been thought that LINC-mediated cytoskeletal forces induce telomere clustering. However, how cytoskeletal forces induce telomere clustering is not fully understood. Recent study of fission yeast has shown that the LINC complex forms the microtubule-organizing center (MTOC) at the telomere, which has been designated as the “telocentrosome”, and that microtubule motors gather telomeres via telocentrosome-nucleated microtubules. This MTOC-dependent telomere clustering might be conserved in other eukaryotes. Furthermore, the MTOC-dependent clustering mechanism appears to function in various other biological events. This review presents an overview of the current understanding of the mechanism of meiotic telomere clustering and discusses the universality of the MTOC-dependent clustering mechanism.     

Telomere dynamics unique to meiotic prophase: formation and significance of the bouquet

Telomeres carry out conserved and possibly ancient functions in meiosis. During the specialized prophase of meiosis I, meiotic prophase, telomeres cluster on the nuclear envelope and move the diploid genetic material around within the nucleus so that homologous chromosomes can align two by two and efficiently recombine with precision. This recombination is in turn required for proper segregation of the homologs into viable haploid daughter cells. The meiosis-specific telomere clustering on the nuclear envelope defines the bouquet stage, so named for its resemblance to the stems from a bouquet of cut flowers. Here, a comparative analysis of the literature on meiotic telomeres from a variety of different species illustrates that the bouquet is nearly universal among life cycles with sexual reproduction. The bouquet has been well documented for over 100 years, but our understanding of how it forms and how it functions has only recently begun to increase. Early and recent observations document the timing and provide clues about the functional significance of these striking telomere movements.     

If the cap fits,wear it: an overview of telomeric structures over evolution

Genome organization into linear chromosomes likely represents an important evolutionary innovation that has permitted the development of the sexual life cycle; this process has consequently advanced nuclear expansion and increased complexity of eukaryotic genomes. Chromosome linearity, however, poses a major challenge to the internal cellular machinery. The need to efficiently recognize and repair DNA double-strand breaks that occur as a consequence of DNA damage presents a constant threat to native chromosome ends known as telomeres. In this review, we present a comparative survey of various solutions to the end protection problem, maintaining an emphasis on DNA structure. This begins with telomeric structures derived from a subset of prokaryotes, mitochondria, and viruses, and will progress into the typical telomere structure exhibited by higher organisms containing TTAGG-like tandem sequences. We next examine non-canonical telomeres from Drosophila melanogaster, which comprise arrays of retrotransposons. Finally, we discuss telomeric structures in evolution and possible switches between canonical and non-canonical solutions to chromosome end protection.     

Composition and conservation of the telomeric complex

The telomere is composed of telomeric DNA and telomere-associated proteins. Recently, many telomere-associated proteins have been identified, and various telomere functions have been uncovered. In budding yeast, scRap1 binds directly to telomeric DNA, and other telomere regulators (Sir proteins and Rif proteins) are recruited to the telomeres by interacting with scRap1. Cdc13 binds to the most distal end of the chromosome and recruits telomerase to the telomeres. In fission yeast and humans, TTAGGG repeat binding factor (TRF) family proteins bind directly to telomeric DNA, and Rap1 proteins and other telomere regulators are recruited to the telomeres by interacting with the TRF family proteins. Both organisms have Pot1 proteins at the most distal end of the telomere instead of a budding-yeast Cdc13-like protein. Therefore, fission yeast and humans have in part common telomeric compositions that differ from that of budding yeast, a result that suggests budding yeast has lost some telomere components during the course of evolution.     

Telomeres and meiosis in health and disease

Meiotic dysfunction increasingly afflicts women as they age, resulting in infertility, miscarriage and handicapped offspring. How aging disrupts meiotic function in women remains unclear, but as women increasingly delay childbearing, this issue becomes urgent. Telomeres, which mediate aging in mitotic cells, may also mediate aging during meiosis. Telomeres shorten during DNA replication. In mammals, oocytes remain quiescent, but their precursors replicated during fetal oogenesis. Moreover, eggs ovulated from older women entered meiosis later during fetal oogenesis than eggs ovulated when younger, and therefore underwent more replications. Telomeres also shorten from reactive oxygen, which triggers a DNA repair response, so the prolonged interval between fetal oogenesis and ovulation in some women would further shorten telomeres. Mice normally do not exhibit age-related meiotic dysfunction (interestingly, their telomeres are manyfold longer than telomeres in women), but genetic or pharmacologic shortening of mouse telomeres recapitulates the reproductive aging phenotype of women. This has led to a telomere theory of age-related meiotic dysfunction in women, and underlined the importance to human health of a mechanistic understanding of telomeres and meiosis.     

Expanding the roles of chromatin insulators in nuclear architecture,chromatin organization and genome function

Of the numerous classes of elements involved in modulating eukaryotic chromosome structure and function, chromatin insulators arguably remain the most poorly understood in their contribution to these processes in vivo. Indeed, our view of chromatin insulators has evolved dramatically since their chromatin boundary and enhancer blocking properties were elucidated roughly a quarter of a century ago as a result of recent genome-wide, high-throughput methods better suited to probing the role of these elements in their native genomic contexts. The overall theme that has emerged from these studies is that chromatin insulators function as general facilitators of higher-order chromatin loop structures that exert both physical and functional constraints on the genome. In this review, we summarize the result of recent work that supports this idea as well as a number of other studies linking these elements to a diverse array of nuclear processes, suggesting that chromatin insulators exert master control over genome organization and behavior.     

Homologous recombination in fission yeast: Absence of crossover interference and synaptonemal complex

The study of homologous recombination in the fission yeastSchizosaccharomyces pombe has recently been extended to the cytological analysis of meiotic prophase. Unlike in most eukaryotes no tripartite SC structure is detectable, but linear elements resembling axial cores of other eukaryotes are retained. They may be indispensable for meiotic recombination and proper chromosome segregation in meiosis I. In addition fission yeast shows interesting features of chromosome organization in vegetative and meiotic cells: Centromeres and telomeres cluster and associate with the spindle pole body. The special properties of fission yeast meiosis correlate with the absence of crossover interference in meiotic recombination. These findings are discussed. In addition homologous recombination in fission yeast is reviewed briefly.This article is dedicated to Urs Leupold, the founder of fission yeast genetics.     

Telomeres and DNA double-strand breaks: ever the twain shall meet?

Telomeres were first recognized as a bona fide constituent of the chromosome based on their inability to rejoin with broken chromosome ends produced by radiation. Today, we recognize two essential and interrelated properties of telomeres. They circumvent the so-called end-replication problem faced by genomes composed of linear chromosomes, which erode from their termini with each successive cell division. Equally vital is the end-capping function that telomeres provide, which is necessary to deter chromosome ends from illicit recombination. This latter property is critical in facilitating the distinction between the naturally occurring DNA double-strand breaks (DSBs) found at chromosome ends (i.e., telomeres) and DSBs produced by exogenous agents. Here we discuss, in a brief historical narrative, key discoveries that led investigators to appreciate the unique properties of telomeres in protecting chromosome ends, and the consequences of telomere dysfunction, particularly as related to recombination involving radiation-induced DSBs. Dedication. In appreciation of his heart-felt commitment to research and education, and the life-long influence he has had on the lives of students and colleagues, the authors wish to dedicate this paper to Professor Joel S. Bedford. Received 21 May 2007; received after revision 28 June 2007; accepted 6 August 2007     

Chromatin structure contribution to the synaptonemal complex formation

Meiosis is a key cellular and molecular process for sexual reproduction contributing to the genetic variability of organisms. This process takes place after DNA replication and consists in a double cellular division, giving rise to four haploid daughter cells or gametes. Meiotic recombination between homologous chromosomes, in the meiotic prophase I, is mediated by a tripartite structure named Synaptonemal Complex (SC). The SC is a peptidic scaffold in which the chromatin of homologous chromosomes is organized during the pachytene stage, holding chromosomes together until the meiotic recombination and genetic exchange have taken place. The role of chromatin structure in formation of the SC and the meiotic recombination at meiotic prophase I remain largely unknown. In this review we address the epigenome contribution to the SC formation at meiotic prophase I, with particular attention on the chromatin structure modifications occurring during the sub-stages of meiotic prophase I. Received 18 September 2008; received after revision 10 October 2008; accepted 24 October 2008     

Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death

Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways. Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands. NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting by the G-quadruplex ligand 360A, leading to cancer cell death.     

Telomeres and chromosomal instability

Telomeres are distinctive structures, composed of a repetitive DNA sequence and associated proteins, which enable cells to distinguish chromosome ends from DNA double-strand breaks. Telomere alterations, caused by replication-mediated shortening, direct damage or defective telomere-associated proteins, usually generate chromosomal instability, which is observed in senescence and during the immortalization process. In cancer cells, this chromosome instability could be extended by their ability to repair chromosomes and terminate in break-fusion-bridge cycles. Dysfunctional telomeres can be healed by activation of telomerase or by the alternative mechanism of telomere lengthening. Activation of such telomere maintenance mechanisms may help to preserve the integrity of chromosomes even if they play a role in chromosomal instability. This review focuses on molecular processes involved in telomere maintenance and chromosomal instability associated with dysfunctional telomeres in mammalian cells.Received 24 July 2003; received after revision 5 September 2003; accepted 11 September 2003     

Telomeres and meiosis in health and disease

The aim of this review is threefold. First, we want to report on recent observations on the role of telomeres in the alignment of homolog and non-homologues in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe and the relationship of early telomere clustering to later recombination events. Second, we compare the similarities and differences between synaptic and asynaptic yeasts. Third, we report on the increasing evidence of the effect of meiosis on telomeric sequences that suggest an induction of a specific form of recombination processes termed telomere rapid deletion.     

Orientation of Giemsa C-bands in interphase cells of Allium cepa L.

Summary Orientation of Giemsa C-bands in Allium cepa was studied in both mitotic and interphase cells. It has been shown that telophase orientation of the chromosome is maintained throughout the interphase and early prophase. It has been assumed that this non-random orientation is due to anchorage of the telomeres with the nuclear membrane. Contrary to earlier observations, 2 by 2 pairing of the telomeres could not be traced in this species.