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Cold Spring Harbor Symposia on Quantitative Biology

Stephen C West, Ying Wai Chan
The efficient processing of homologous recombination (HR) intermediates, which often contain four-way structures known as Holliday junctions (HJs), is required for proper chromosome segregation at mitosis. Eukaryotic cells possess three distinct pathways of resolution: (i) HJ dissolution mediated by BLM-topoisomerase IIIα-RMI1-RMI2 (BTR) complex, and HJ resolution catalyzed by either (ii) SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX complex) or (iii) GEN1. The BTR pathway acts at all times throughout the cell cycle, whereas the actions of SMX and GEN1 are restrained in S phase and become elevated late in the cell cycle to ensure the resolution of persistent recombination intermediates before mitotic division...
January 18, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Elizabeth W Kahney, Rajesh Ranjan, Ryan J Gleason, Xin Chen
The processes of DNA replication and mitosis allow the genetic information of a cell to be copied and transferred reliably to its daughter cells. However, if DNA replication and cell division were always performed in a symmetric manner, the result would be a cluster of tumor cells instead of a multicellular organism. Therefore, gaining a complete understanding of any complex living organism depends on learning how cells become different while faithfully maintaining the same genetic material. It is well recognized that the distinct epigenetic information contained in each cell type defines its unique gene expression program...
January 18, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Katherine C Palozola, Hong Liu, Dario Nicetto, Kenneth S Zaret
Mitosis is thought to be a period of transcriptional silence due to the compact nature of mitotic chromosomes and the apparent exclusion of RNA Pol II and many transcription factors from mitotic chromatin. Yet accurate reactivation of a cell's specific gene expression program is needed to reestablish functional cell identity after mitosis. The majority of studies on protein regulation and localization during mitosis have relied extensively on antibodies and cross-linking-based approaches that are known to artifactually exclude proteins from mitotic chromatin...
January 18, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Takamune T Saito, Monica P Colaiácovo
Crossover recombination is essential for generating genetic diversity and promoting accurate chromosome segregation during meiosis. The process of crossover recombination is tightly regulated and is initiated by the formation of programmed meiotic DNA double-strand breaks (DSBs). The number of DSBs is around 10-fold higher than the number of crossovers in most species, because only a limited number of DSBs are repaired as crossovers during meiosis. Moreover, crossovers are not randomly distributed. Most crossovers are located on chromosomal arm regions and both centromeres and telomeres are usually devoid of crossovers...
December 8, 2017: Cold Spring Harbor Symposia on Quantitative Biology
David Sitbon, Katrina Podsypanina, Tejas Yadav, Geneviève Almouzni
Chromatin organization in the nucleus provides a vast repertoire of information in addition to that encoded genetically. Understanding how this organization impacts genome stability and influences cell fate and tumorigenesis is an area of rapid progress. Considering the nucleosome, the fundamental unit of chromatin structure, the study of histone variants (the bricks) and their selective loading by histone chaperones (the architects) is particularly informative. Here, we report recent advances in understanding how relationships between histone variants and their chaperones contribute to tumorigenesis using cell lines and Xenopus development as model systems...
December 5, 2017: Cold Spring Harbor Symposia on Quantitative Biology
So I Nagaoka, Mitinori Saitou
Meiosis is a fundamental process that underpins sexual reproduction. In mammals, the execution of meiosis is tightly integrated within the complex processes of oogenesis and spermatogenesis, and elucidation of the molecular mechanisms regulating meiotic initiation remains challenging. We have recently developed in vitro culture strategies to induce mouse pluripotent stem cells into germ cells, which successfully contribute to both oogenesis and spermatogenesis and to fertile offspring. The culture strategies faithfully recapitulate transcriptional and epigenetic dynamics as well as signaling principles for germ cell specification, proliferation, and female sex determination/meiotic induction, providing a valuable platform for studies to illuminate the molecular mechanisms underlying such critical processes...
December 5, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Sarah C Hsu, Gerd A Blobel
Bromodomain and extraterminal motif (BET) proteins have been widely investigated for their roles in gene regulation and their potential as therapeutic targets in cancer. Pharmacologic BET inhibitors target the conserved bromodomain-acetyllysine interaction and do not distinguish between BRD2, BRD3, and BRD4. Thus, comparatively little is known regarding the distinct roles played by individual family members, as well as the underlying mechanisms that drive the transcriptional effects of BET inhibitors. Here we review studies regarding the contributions of BET proteins to genome structure and function, including recent work identifying a role for BRD2 as a component of functional and physical chromatin domain boundaries...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Seira Miyazaki, Jihye Kim, Takeshi Sakuno, Yoshinori Watanabe
The kinetochore is the key apparatus regulating chromosome segregation. Particularly in meiosis, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation), and sister chromatid cohesion mediated by cohesin is protected at centromeres in the following anaphase. Shugoshin, which localizes to centromeres depending on the phosphorylation of histone H2A by Bub1 kinase, plays a central role in protecting meiotic cohesin Rec8 from separase cleavage...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Timothy J Mitchison, Christine M Field
During cytokinesis, the mitotic spindle communicates with the cell cortex to position a cleavage furrow that will cut through the cell in the plane defined by the metaphase plate. We investigated the molecular basis of this communication in Xenopus laevis eggs, where the signal has to travel ∼400 µm in ∼30 min to reach the cortex from the first anaphase spindle. At anaphase onset, huge microtubule asters grow out from the poles of the spindle and meet at the plane previously defined by the metaphase plate...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Steven Henikoff, Jitendra Thakur, Sivakanthan Kasinathan, Paul B Talbert
Centromeres were familiar to cell biologists in the late 19th century, but for most eukaryotes the basis for centromere specification has remained enigmatic. Much attention has been focused on the cenH3 (CENP-A) histone variant, which forms the foundation of the centromere. To investigate the DNA sequence requirements for centromere specification, we applied a variety of epigenomic approaches, which have revealed surprising diversity in centromeric chromatin properties. Whereas each point centromere of budding yeast is occupied by a single precisely positioned tetrameric nucleosome with one cenH3 molecule, the "regional" centromeres of fission yeast contain unphased presumably octameric nucleosomes with two cenH3s...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Prabhakar R Gudla, Koh Nakayama, Gianluca Pegoraro, Tom Misteli
DNA fluorescence in situ hybridization (FISH) is the technique of choice to map the position of genomic loci in three-dimensional (3D) space at the single allele level in the cell nucleus. High-throughput DNA FISH methods have recently been developed using complex libraries of fluorescently labeled synthetic oligonucleotides and automated fluorescence microscopy, enabling large-scale interrogation of genomic organization. Although the FISH signals generated by high-throughput methods can, in principle, be analyzed by traditional spot-detection algorithms, these approaches require user intervention to optimize each interrogated genomic locus, making analysis of tens or hundreds of genomic loci in a single experiment prohibitive...
November 28, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Simon Jenni, Yoana N Dimitrova, Roberto Valverde, Stephen M Hinshaw, Stephen C Harrison
Kinetochore molecular architecture exemplifies "form follows function." The simplifications that generated the one-chromosome:one-microtubule linkage in point-centromere yeast have enabled strategies for systematic structural analysis and high-resolution visualization of many kinetochore components, leading to specific proposals for molecular mechanisms. We describe here some structural features that allow a kinetochore to remain attached to the end of a depolymerizing microtubule (MT) and some characteristics of the connections between substructures that permit very sensitive regulation by differential kinase activities...
November 22, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Josh Lawrimore, Brandon Friedman, Ayush Doshi, Kerry Bloom
ChromoShake is a three-dimensional simulator designed to explore the range of configurational states a chromosome can adopt based on thermodynamic fluctuations of the polymer chain. Here, we refine ChromoShake to generate dynamic simulations of a DNA-based motor protein such as condensin walking along the chromatin substrate. We model walking as a rotation of DNA-binding heat-repeat proteins around one another. The simulation is applied to several configurations of DNA to reveal the consequences of mechanical stepping on taut chromatin under tension versus loop extrusion on single-tethered, floppy chromatin substrates...
November 22, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Ping Chen, Guohong Li
In eukaryotes, genomic DNA is hierarchically packaged by histones into chromatin on several levels to fit inside the nucleus. As a central-level structure between nucleosomal arrays and higher-order chromatin organizations, the 30-nm chromatin fiber and its dynamics play a crucial role in gene regulation. However, despite considerable efforts over the past three decades, the fundamental structure and its dynamic regulation of chromatin fibers still remain as a big challenge in molecular biology. Here, we mainly summarize the most recent progress in elucidating the structure of the 30-nm chromatin fiber in vitro and epigenetic regulation of chromatin fibers by chromatin factors, particularly histone variants...
November 22, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Allan C Spradling
Polytene chromosomes have for 80 years provided the highest resolution view of interphase genome structure in an animal cell nucleus. These chromosomes represent the normal genomic state of nearly all Drosophila larval and many adult cells, and a better understanding of their striking banded structure has been sought for decades. A more recently appreciated characteristic of Drosophila polytene cells is somatic genome instability caused by unfinished replication (UR). Repair of stalled forks generates enough deletions in polytene salivary gland cells to alter 10%-90% of the DNA strands within more than 100 UR regions comprising 20% of the euchromatic genome...
November 22, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Kata Sarlós, Andreas Biebricher, Erwin J G Petermann, Gijs J L Wuite, Ian D Hickson
To survive and proliferate, cells have to faithfully segregate their newly replicated genomic DNA to the two daughter cells. However, the sister chromatids of mitotic chromosomes are frequently interlinked by so-called ultrafine DNA bridges (UFBs) that are visible in the anaphase of mitosis. UFBs can only be detected by the proteins bound to them and not by staining with conventional DNA dyes. These DNA bridges are presumed to represent entangled sister chromatids and hence pose a threat to faithful segregation...
November 22, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Pablo Lara-Gonzalez, Taekyung Kim, Arshad Desai
The anaphase-promoting complex/cyclosome (APC/C) is a large multisubunit ubiquitin ligase that triggers the metaphase-to-anaphase transition in the cell cycle by targeting the substrates cyclin B and securin for destruction. APC/C activity toward these two key substrates requires the coactivator Cdc20. To ensure that cells enter mitosis and partition their duplicated genome with high accuracy, APC/C(Cdc20) activity must be tightly controlled. Here, we discuss the mechanisms that regulate APC/C(Cdc20) activity both before and during mitosis...
November 13, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Peter Zeller, Susan M Gasser
Up to two-thirds of eukaryotic genomes consist of repetitive sequences, which include both transposable elements and tandemly arranged simple or satellite repeats. Whereas extensive progress has been made toward understanding the danger of and control over transposon expression, only recently has it been recognized that DNA damage can arise from satellite sequence transcription. Although the structural role of satellite repeats in kinetochore function and end protection has long been appreciated, it has now become clear that it is not only these functions that are compromised by elevated levels of transcription...
November 13, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Keishi Shintomi, Tatsuya Hirano
The mitotic chromosome is a macromolecular assembly that ensures error-free transmission of the genome during cell division. It has long been a big mystery how long stretches of DNA might be folded into rod-shaped chromosomes or how such an elaborate process might be accomplished at a mechanistic level. Cell-free extracts made from frog eggs offer a unique opportunity to address these questions by enabling mitotic chromosomes to be assembled in a test tube. Moreover, the core part of the chromosome assembly reaction can now be reconstituted with a limited number of purified factors...
November 8, 2017: Cold Spring Harbor Symposia on Quantitative Biology
Joanna Achinger-Kawecka, Phillippa C Taberlay, Susan J Clark
The structural and functional basis of the genome is provided by the three-dimensional (3D) chromatin state. To enable accurate gene regulation, enhancer elements and promoter regions are brought into close spatial proximity to ensure proper, cell type-specific gene expression. In cancer, genetic and epigenetic processes can deregulate the transcriptional program. To investigate whether the 3D chromatin state is also disrupted in cancer we performed Hi-C chromosome conformation sequencing in normal and prostate cancer cells and compared the chromatin interaction maps with changes to the genome and epigenome...
April 19, 2017: Cold Spring Harbor Symposia on Quantitative Biology
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