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Kaykov A.,Rockefeller University | Nurse P.,Rockefeller University | Nurse P.,Francis Crick Institute
Genome Research | Year: 2015

Eukaryotes duplicate their genomes using multiple replication origins, but the organization of origin firing along chromosomes and during S-phase is not well understood. Using fission yeast, we report the first genome-wide analysis of the spatial and temporal organization of replication origin firing, analyzed using single DNA molecules that can approach the full length of chromosomes. At S-phase onset, origins fire randomly and sparsely throughout the chromosomes. Later in S-phase, clusters of fired origins appear embedded in the sparser regions, which form the basis of nuclear replication foci. The formation of clusters requires proper histone methylation and acetylation, and their locations are not inherited between cell cycles. The rate of origin firing increases gradually, peaking just before mid S-phase. Toward the end of S-phase, nearly all the available origins within the unreplicated regions are fired, contributing to the timely completion of genome replication. We propose that the majority of origins do not fire as a part of a deterministic program. Instead, origin firing, both individually and as clusters, should be viewed as being mostly stochastic. © 2015 Kaykov and Nurse. Source

Singleton M.R.,Francis Crick Institute
Open Biology | Year: 2016

The Mis12 complex forms the central scaffold of the kinetochore and serves to bridge the chromatin and microtubule-binding activities of the inner and outer layers, respectively. Two recent studies provide new structural insights into the formation of this complex, and highlight some intriguing adaptations found in the Drosophila kinetochore. © 2016 The Authors. Source

Wu P.-Y.,University of Rennes 2 - Upper Brittany | Wu P.-Y.,Rockefeller University | Nurse P.,Rockefeller University | Nurse P.,Francis Crick Institute
Molecular Cell | Year: 2014

The program of DNA replication, defined by the temporal and spatial pattern of origin activation, is altered during development and in cancers. However, whether changes in origin usage play a role in regulating specific biological processes remains unknown. We investigated the consequences of modifying origin selection on meiosis in fission yeast. Genome-wide changes in the replication program of premeiotic S phase do not affect meiotic progression, indicating that meiosis neither activates nor requires a particular origin pattern. In contrast, local changes in origin efficiencies between different replication programs lead to changes in Rad51 recombination factor binding and recombination frequencies in these domains. We observed similar results for Rad51 when changes in efficiencies were generated by directly targeting expression of the Cdc45 replication factor. We conclude that origin selection is a keydeterminant for organizing meiotic recombination, providing evidence that genome-wide modifications in replication program can modulate cellular physiology. © 2014 Elsevier Inc. Source

Turner J.M.A.,Francis Crick Institute
Annual Review of Genetics | Year: 2015

Meiosis is essential for reproduction in sexually reproducing organisms. A key stage in meiosis is the synapsis of maternal and paternal homologous chromosomes, accompanied by exchange of genetic material to generate crossovers. A decade ago, studies found that when chromosomes fail to synapse, the many hundreds of genes housed within them are transcriptionally inactivated. This process, meiotic silencing, is conserved in all mammals studied to date, but its purpose is not yet defined. Here, I review the molecular genetics of meiotic silencing and consider the many potential functions that it could serve in the mammalian germ line. In addition, I discuss how meiotic silencing influences sex differences in meiotic infertility and the profound impact that meiotic silencing has had on the evolution of mammalian sex chromosomes. Copyright © 2015 by Annual Reviews. All rights reserved. Source

Proteins have many functions and predicting these is still one of the major challenges in theoretical biophysics and bioinformatics. Foremost amongst these functions is the need to fold correctly thereby allowing the other genetically dictated tasks that the protein has to carry out to proceed efficiently. In this work, some earlier algorithms for predicting protein domain folds are revisited and they are compared with more recently developed methods. In dealing with intractable problems such as fold prediction, when different algorithms show convergence onto the same result there is every reason to take all algorithms into account such that a consensus result can be arrived at. In this work it is shown that the application of different algorithms in protein structure prediction leads to results that do not converge as such but rather they collude in a striking and useful way that has never been considered before. © 2016 Robert P. Bywater.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author an source are credited. Source

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