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Progress in Molecular and Subcellular Biology

Thian Thian Beh, Paul Kalitsis
The accurate segregation of chromosomes to daughter cells is essential for healthy development to occur. Imbalances in chromosome number have long been associated with cancers amongst other medical disorders. Little is known whether abnormal chromosome numbers are an early contributor to the cancer progression pathway. Centromere DNA and protein defects are known to impact on the fidelity of chromosome segregation in cell and model systems. In this chapter we discuss recent developments in understanding the contribution of centromere abnormalities at the protein and DNA level and their role in cancer in human and mouse systems...
2017: Progress in Molecular and Subcellular Biology
Kerry Bloom, Vincenzo Costanzo
The centromere is the genetic locus that specifies the site of kinetochore assembly, where the chromosome will attach to the kinetochore microtubule. The pericentromere is the physical region responsible for the geometry of bi-oriented sister kinetochores in metaphase. In budding yeast the 125 bp point centromere is sufficient to specify kinetochore assembly. The flanking region is enriched (3X) in cohesin and condensin relative to the remaining chromosome arms. The enrichment spans about 30-50 kb around each centromere...
2017: Progress in Molecular and Subcellular Biology
Mihailo Mirkovic, Raquel A Oliveira
Sister chromatid cohesion, mediated by the cohesin complex, is a prerequisite for faithful chromosome segregation during mitosis. Premature release of sister chromatid cohesion leads to random segregation of the genetic material and consequent aneuploidy. Multiple regulatory mechanisms ensure proper timing for cohesion establishment, concomitant with DNA replication, and cohesion release during the subsequent mitosis. Here we summarize the most important phases of the cohesin cycle and the coordination of cohesion release with the progression through mitosis...
2017: Progress in Molecular and Subcellular Biology
Giulia Vallardi, Marilia Henriques Cordeiro, Adrian Thomas Saurin
The KMN network (for KNL1, MIS12 and NDC80 complexes) is a hub for signalling at the outer kinetochore. It integrates the activities of two kinases (MPS1 and Aurora B) and two phosphatases (PP1 and PP2A-B56) to regulate kinetochore-microtubule attachments and the spindle assembly checkpoint (SAC). We will first discuss each of these enzymes separately, to describe how they are regulated at kinetochores and why this is important for their primary function in controlling either microtubule attachments or the SAC...
2017: Progress in Molecular and Subcellular Biology
Kevin D Corbett
In eukaryotic cell division, the Spindle Assembly Checkpoint (SAC) plays a key regulatory role by monitoring the status of chromosome-microtubule attachments and allowing chromosome segregation only after all chromosomes are properly attached to spindle microtubules. While the identities of SAC components have been known, in some cases, for over two decades, the molecular mechanisms of the SAC have remained mostly mysterious until very recently. In the past few years, advances in biochemical reconstitution, structural biology, and bioinformatics have fueled an explosion in the molecular understanding of the SAC...
2017: Progress in Molecular and Subcellular Biology
Ekaterina L Grishchuk
The main physiological function of mitotic kinetochores is to provide durable attachment to spindle microtubules, which segregate chromosomes in order to partition them equally between the two daughter cells. Numerous kinetochore components that can bind directly to microtubules have been identified, including ATP-dependent motors and various microtubule-associated proteins with no motor activity. A major challenge facing the field is to explain chromosome motions based on the biochemical and structural properties of these individual kinetochore components and their assemblies...
2017: Progress in Molecular and Subcellular Biology
Lukáš Chmátal, Richard M Schultz, Ben E Black, Michael A Lampson
Mendel's First Law of Genetics states that a pair of alleles segregates randomly during meiosis so that one copy of each is represented equally in gametes. Whereas male meiosis produces four equal sperm, in female meiosis only one cell, the egg, survives, and the others degenerate. Meiotic drive is a process in which a selfish DNA element exploits female meiotic asymmetry and segregates preferentially to the egg in violation of Mendel's First Law, thereby increasing its transmission to the offspring and frequency in a population...
2017: Progress in Molecular and Subcellular Biology
Elaine M Dunleavy, Caitríona M Collins
In sexually reproducing organisms the germ line is the cellular lineage that gives rise to gametes. All germ cells originate from germline stem cells that divide asymmetrically to generate gonial pre-cursors, which are amplified in number by mitotic divisions, undergo meiosis and eventually differentiate into mature gametes (haploid eggs and sperm). Information transmitted with gametes is inherited by offspring, and potentially by subsequent generations, instructing in organismal development and beyond. Meiosis comprises one round of DNA replication, followed by two rounds of chromosome segregation; homologous chromosomes segregate in the first division (meiosis I) and sister chromatids segregate in the second division (meiosis II)...
2017: Progress in Molecular and Subcellular Biology
Elena Giulotto, Elena Raimondi, Kevin F Sullivan
Centromeres are highly distinctive genetic loci whose function is specified largely by epigenetic mechanisms. Understanding the role of DNA sequences in centromere function has been a daunting task due to the highly repetitive nature of centromeres in animal chromosomes. The discovery of a centromere devoid of satellite DNA in the domestic horse consolidated observations on the epigenetic nature of centromere identity, showing that entirely natural chromosomes could function without satellite DNA cues. Horses belong to the genus Equus which exhibits a very high degree of evolutionary plasticity in centromere position and DNA sequence composition...
2017: Progress in Molecular and Subcellular Biology
M Dumont, D Fachinetti
Faithful chromosome segregation during cell division depends on the centromere, a complex DNA/protein structure that links chromosomes to spindle microtubules. This chromosomal domain has to be marked throughout cell division and its chromosomal localization preserved across cell generations. From fission yeast to human, centromeres are established on a series of repetitive DNA sequences and on specialized centromeric chromatin. This chromatin is enriched with the histone H3 variant, named CENP-A, that was demonstrated to be the epigenetic mark that maintains centromere identity and function indefinitely...
2017: Progress in Molecular and Subcellular Biology
Karen H Miga
Human centromeres are genomic regions that act as sites of kinetochore assembly to ensure proper chromosome segregation during mitosis and meiosis. Although the biological importance of centromeres in genome stability, and ultimately, cell viability are well understood, the complete sequence content and organization in these multi-megabase-sized regions remains unknown. The lack of a high-resolution reference assembly inhibits standard bioinformatics protocols, and as a result, sequence-based studies involving human centromeres lag far behind the advances made for the non-repetitive sequences in the human genome...
2017: Progress in Molecular and Subcellular Biology
Zachary Duda, Sarah Trusiak, Rachel O'Neill
The chromosome biology field at large has benefited from studies of the cell cycle components, protein cascades and genomic landscape that are required for centromere identity, assembly and stable transgenerational inheritance. Research over the past 20 years has challenged the classical descriptions of a centromere as a stable, unmutable, and transcriptionally silent chromosome component. Instead, based on studies from a broad range of eukaryotic species, including yeast, fungi, plants, and animals, the centromere has been redefined as one of the more dynamic areas of the eukaryotic genome, requiring coordination of protein complex assembly, chromatin assembly, and transcriptional activity in a cell cycle specific manner...
2017: Progress in Molecular and Subcellular Biology
Shannon M McNulty, Beth A Sullivan
Centromere function is essential for genome stability and chromosome inheritance. Typically, each chromosome has a single locus that consistently serves as the site of centromere formation and kinetochore assembly. Decades of research have defined the DNA sequence and protein components of functional centromeres, and the interdependencies of specific protein complexes for proper centromere assembly. Less is known about how centromeres are disassembled or functionally silenced. Centromere silencing, or inactivation, is particularly relevant in the cases of dicentric chromosomes that occur via genome rearrangements that place two centromeres on the same chromosome...
2017: Progress in Molecular and Subcellular Biology
Ana García Del Arco, Sylvia Erhardt
Regulation of chromatin structures is important for the control of DNA processes such as gene expression, and misregulation of chromatin is implicated in diverse diseases. Covalent post-translational modifications of histones are a prominent way to regulate chromatin structure and different chromatin regions bear their specific signature of histone modifications. The composition of centromeric chromatin is significantly different from other chromatin structures and mainly defined by the presence of the histone H3-variant CENP-A...
2017: Progress in Molecular and Subcellular Biology
Evelyne J Barrey, Patrick Heun
In recent years, various synthetic approaches have been developed to address the question of what directs centromere establishment and maintenance. In this chapter, we will discuss how approaches aimed at constructing synthetic centromeres have co-evolved with and contributed to shape the theory describing the determinants of centromere identity. We will first review lessons learned from artificial chromosomes created from "naked" centromeric sequences to investigate the role of the underlying DNA for centromere formation...
2017: Progress in Molecular and Subcellular Biology
Ewelina Zasadzińska, Daniel R Foltz
Centromeres are chromosomal loci that are defined epigenetically in most eukaryotes by incorporation of a centromere-specific nucleosome in which the canonical histone H3 variant is replaced by Centromere Protein A (CENP-A). Therefore, the assembly and propagation of centromeric nucleosomes are critical for maintaining centromere identify and ensuring genomic stability. Centromeres direct chromosome segregation (during mitosis and meiosis) by recruiting the constitutive centromere-associated network of proteins throughout the cell cycle that in turn recruits the kinetochore during mitosis...
2017: Progress in Molecular and Subcellular Biology
Ana Stankovic, Lars E T Jansen
Centromeres are chromatin domains specified by nucleosomes containing the histone H3 variant, CENP-A. This unique centromeric structure is at the heart of a strong self-templating epigenetic mechanism that renders centromeres heritable. We review how specific quantitative microscopy approaches have contributed to the determination of the copy number, architecture, size, and dynamics of centromeric chromatin and its associated centromere complex and kinetochore. These efforts revealed that the key to long-term centromere maintenance is the slow turnover of CENP-A nucleosomes, a critical size of the chromatin domain and its cell cycle-coupled replication...
2017: Progress in Molecular and Subcellular Biology
Ines A Drinnenberg, Bungo Akiyoshi
The kinetochore is the multi-protein complex that drives chromosome segregation in eukaryotes. It assembles onto centromeric DNA and mediates attachment to spindle microtubules. Kinetochore research over the last several decades has been focused on a few animal and fungal model organisms, which revealed a detailed understanding of the composition and organization of their kinetochores. Yet, these traditional model organisms represent only a small fraction of all eukaryotes. To gain insights into the actual degree of kinetochore diversity, it is critical to extend these studies to nontraditional model organisms from evolutionarily distant lineages...
2017: Progress in Molecular and Subcellular Biology
Steven Friedman, Michael Freitag
The centromere is an essential chromosomal locus that dictates the nucleation point for assembly of the kinetochore and subsequent attachment of spindle microtubules during chromosome segregation. Research over the last decades demonstrated that centromeres are defined by a combination of genetic and epigenetic factors. Recent work showed that centromeres are quite diverse and flexible and that many types of centromere sequences and centromeric chromatin ("centrochromatin") have evolved. The kingdom of the fungi serves as an outstanding example of centromere plasticity, including organisms with centromeres as diverse as 0...
2017: Progress in Molecular and Subcellular Biology
Bradley T French, Aaron F Straight
Faithful transmission of genetic information during cell division requires attachment of chromosomes to the mitotic spindle via the kinetochore. In vitro reconstitution studies are beginning to uncover how the kinetochore is assembled upon the underlying centromere, how the kinetochore couples chromosome movement to microtubule dynamics, and how cells ensure the site of kinetochore assembly is maintained from one generation to the next. Here we give special emphasis to advances made in Xenopus egg extract, which provides a unique, biochemically tractable in vitro system that affords the complexity of cytoplasm and nucleoplasm to permit reconstitution of the dynamic, cell cycle-regulated functions of the centromere and kinetochore...
2017: Progress in Molecular and Subcellular Biology
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