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DNA Replication Timing: Where, When, How and Why?
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DNA Replication Timing: Where, When, How and Why?

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 42548

Special Issue Editor

Dr. Amnon Koren

E-Mail Website
Guest Editor
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
Interests: DNA replication timing; mutations; genomics; human genetics; copy number variation

Special Issue Information

Dear Colleagues,

DNA replication is the molecular basis of inheritance. Eukaryotic genomes are replicated from numerous DNA replication origins, which are activated at different times along S phase. The study of DNA replication timing has proven particularly challenging, with many fundamental questions remaining largely unresolved. For instance, where are DNA replication origins located across the genomes of higher eukaryotes? What are the mechanisms that lead to specific genomic loci functioning as replication origins? And even, what is the chromosomal nature of replication initiation sites—are they single loci, clusters of redundant initiating sites, or broader chromosomal domains? Similarly, we still have poor understanding of the mechanisms that determine the time of activation of particular replication origins.  While the biochemistry of replication initiation has been studied in great detail (not withstanding several hotly debated questions), it remains largely unknown how regulation of DNA replication timing is carried out. Another fundamental question that remains incompletely resolved is: why do cells have a DNA replication timing program? Is it important that certain genomic regions replicate early while others replicate late? For instance, does replication timing influence genome regulation and cellular and organismal physiology? Exciting new approaches are being utilized to explore these questions and have established or revealed new links between replication timing and gene regulation, chromatin structure, chromosome conformation, mutational processes, inheritance, diseases, and more. These discoveries are leading to a revived and expanded interest in DNA replication timing and are sure to bring a new level of understanding of this important process in the forthcoming years. This Special Issue addresses DNA replication timing in various species from all of these different aspects: causes, consequences, properties, and mechanisms.

Dr. Amnon Koren
Guest Editor

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Keywords

  • DNA replication timing
  • DNA replication origin
  • Genome regulation
  • DNA copy number
  • S phase
  • Cell cycle
  • Genome stability

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Published Papers (7 papers)

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Research

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12 pages, 4612 KiB  
Communication
Next-Generation Sequencing Enables Spatiotemporal Resolution of Human Centromere Replication Timing
by Dashiell J. Massey, Dongsung Kim, Kayla E. Brooks, Marcus B. Smolka and Amnon Koren
Genes 2019, 10(4), 269; https://doi.org/10.3390/genes10040269 - 2 Apr 2019
Cited by 20 | Viewed by 4805
Abstract
Centromeres serve a critical function in preserving genome integrity across sequential cell divisions, by mediating symmetric chromosome segregation. The repetitive, heterochromatic nature of centromeres is thought to be inhibitory to DNA replication, but has also led to their underrepresentation in human reference genome [...] Read more.
Centromeres serve a critical function in preserving genome integrity across sequential cell divisions, by mediating symmetric chromosome segregation. The repetitive, heterochromatic nature of centromeres is thought to be inhibitory to DNA replication, but has also led to their underrepresentation in human reference genome assemblies. Consequently, centromeres have been excluded from genomic replication timing analyses, leaving their time of replication unresolved. However, the most recent human reference genome, hg38, included models of centromere sequences. To establish the experimental requirements for achieving replication timing profiles for centromeres, we sequenced G1- and S-phase cells from five human cell lines, and aligned the sequence reads to hg38. We were able to infer DNA replication timing profiles for the centromeres in each of the five cell lines, which showed that centromere replication occurs in mid-to-late S phase. Furthermore, we found that replication timing was more variable between cell lines in the centromere regions than expected, given the distribution of variation in replication timing genome-wide. These results suggest the potential of these, and future, sequence models to enable high-resolution studies of replication in centromeres and other heterochromatic regions. Full article
(This article belongs to the Special Issue DNA Replication Timing: Where, When, How and Why?)
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14 pages, 7360 KiB  
Communication
Cohesin-Mediated Genome Architecture Does Not Define DNA Replication Timing Domains
by Phoebe Oldach and Conrad A. Nieduszynski
Genes 2019, 10(3), 196; https://doi.org/10.3390/genes10030196 - 4 Mar 2019
Cited by 14 | Viewed by 5367
Abstract
3D genome organization is strongly predictive of DNA replication timing in mammalian cells. This work tested the extent to which loop-based genome architecture acts as a regulatory unit of replication timing by using an auxin-inducible system for acute cohesin ablation. Cohesin ablation in [...] Read more.
3D genome organization is strongly predictive of DNA replication timing in mammalian cells. This work tested the extent to which loop-based genome architecture acts as a regulatory unit of replication timing by using an auxin-inducible system for acute cohesin ablation. Cohesin ablation in a population of cells in asynchronous culture was shown not to disrupt patterns of replication timing as assayed by replication sequencing (RepliSeq) or BrdU-focus microscopy. Furthermore, cohesin ablation prior to S phase entry in synchronized cells was similarly shown to not impact replication timing patterns. These results suggest that cohesin-mediated genome architecture is not required for the execution of replication timing patterns in S phase, nor for the establishment of replication timing domains in G1. Full article
(This article belongs to the Special Issue DNA Replication Timing: Where, When, How and Why?)
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14 pages, 1904 KiB  
Article
H3K9 Promotes Under-Replication of Pericentromeric Heterochromatin in Drosophila Salivary Gland Polytene Chromosomes
by Robin L. Armstrong, Taylor J. R. Penke, Samuel K. Chao, Gabrielle M. Gentile, Brian D. Strahl, A. Gregory Matera, Daniel J. McKay and Robert J. Duronio
Genes 2019, 10(2), 93; https://doi.org/10.3390/genes10020093 - 29 Jan 2019
Cited by 12 | Viewed by 5792
Abstract
Chromatin structure and its organization contributes to the proper regulation and timing of DNA replication. Yet, the precise mechanism by which chromatin contributes to DNA replication remains incompletely understood. This is particularly true for cell types that rely on polyploidization as a developmental [...] Read more.
Chromatin structure and its organization contributes to the proper regulation and timing of DNA replication. Yet, the precise mechanism by which chromatin contributes to DNA replication remains incompletely understood. This is particularly true for cell types that rely on polyploidization as a developmental strategy for growth and high biosynthetic capacity. During Drosophila larval development, cells of the salivary gland undergo endoreplication, repetitive rounds of DNA synthesis without intervening cell division, resulting in ploidy values of ~1350C. S phase of these endocycles displays a reproducible pattern of early and late replicating regions of the genome resulting from the activity of the same replication initiation factors that are used in diploid cells. However, unlike diploid cells, the latest replicating regions of polyploid salivary gland genomes, composed primarily of pericentric heterochromatic enriched in H3K9 methylation, are not replicated each endocycle, resulting in under-replicated domains with reduced ploidy. Here, we employ a histone gene replacement strategy in Drosophila to demonstrate that mutation of a histone residue important for heterochromatin organization and function (H3K9) but not mutation of a histone residue important for euchromatin function (H4K16), disrupts proper endoreplication in Drosophila salivary gland polyploid genomes thereby leading to DNA copy gain in pericentric heterochromatin. These findings reveal that H3K9 is necessary for normal levels of under-replication of pericentric heterochromatin and suggest that under-replication at pericentric heterochromatin is mediated through H3K9 methylation. Full article
(This article belongs to the Special Issue DNA Replication Timing: Where, When, How and Why?)
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Review

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12 pages, 881 KiB  
Review
Insights into the Link between the Organization of DNA Replication and the Mutational Landscape
by Julia Gaboriaud and Pei-Yun Jenny Wu
Genes 2019, 10(4), 252; https://doi.org/10.3390/genes10040252 - 27 Mar 2019
Cited by 16 | Viewed by 3782
Abstract
The generation of a complete and accurate copy of the genetic material during each cell cycle is integral to cell growth and proliferation. However, genetic diversity is essential for adaptation and evolution, and the process of DNA replication is a fundamental source of [...] Read more.
The generation of a complete and accurate copy of the genetic material during each cell cycle is integral to cell growth and proliferation. However, genetic diversity is essential for adaptation and evolution, and the process of DNA replication is a fundamental source of mutations. Genome alterations do not accumulate randomly, with variations in the types and frequencies of mutations that arise in different genomic regions. Intriguingly, recent studies revealed a striking link between the mutational landscape of a genome and the spatial and temporal organization of DNA replication, referred to as the replication program. In our review, we discuss how this program may contribute to shaping the profile and spectrum of genetic alterations, with implications for genome dynamics and organismal evolution in natural and pathological contexts. Full article
(This article belongs to the Special Issue DNA Replication Timing: Where, When, How and Why?)
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23 pages, 2096 KiB  
Review
DNA Replication Timing Enters the Single-Cell Era
by Ichiro Hiratani and Saori Takahashi
Genes 2019, 10(3), 221; https://doi.org/10.3390/genes10030221 - 15 Mar 2019
Cited by 12 | Viewed by 7143
Abstract
In mammalian cells, DNA replication timing is controlled at the level of megabase (Mb)-sized chromosomal domains and correlates well with transcription, chromatin structure, and three-dimensional (3D) genome organization. Because of these properties, DNA replication timing is an excellent entry point to explore genome [...] Read more.
In mammalian cells, DNA replication timing is controlled at the level of megabase (Mb)-sized chromosomal domains and correlates well with transcription, chromatin structure, and three-dimensional (3D) genome organization. Because of these properties, DNA replication timing is an excellent entry point to explore genome regulation at various levels and a variety of studies have been carried out over the years. However, DNA replication timing studies traditionally required at least tens of thousands of cells, and it was unclear whether the replication domains detected by cell population analyses were preserved at the single-cell level. Recently, single-cell DNA replication profiling methods became available, which revealed that the Mb-sized replication domains detected by cell population analyses were actually well preserved in individual cells. In this article, we provide a brief overview of our current knowledge on DNA replication timing regulation in mammals based on cell population studies, outline the findings from single-cell DNA replication profiling, and discuss future directions and challenges. Full article
(This article belongs to the Special Issue DNA Replication Timing: Where, When, How and Why?)
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21 pages, 2590 KiB  
Review
Origin Firing Regulations to Control Genome Replication Timing
by Dominik Boos and Pedro Ferreira
Genes 2019, 10(3), 199; https://doi.org/10.3390/genes10030199 - 6 Mar 2019
Cited by 38 | Viewed by 7769
Abstract
Complete genome duplication is essential for genetic homeostasis over successive cell generations. Higher eukaryotes possess a complex genome replication program that involves replicating the genome in units of individual chromatin domains with a reproducible order or timing. Two types of replication origin firing [...] Read more.
Complete genome duplication is essential for genetic homeostasis over successive cell generations. Higher eukaryotes possess a complex genome replication program that involves replicating the genome in units of individual chromatin domains with a reproducible order or timing. Two types of replication origin firing regulations ensure complete and well-timed domain-wise genome replication: (1) the timing of origin firing within a domain must be determined and (2) enough origins must fire with appropriate positioning in a short time window to avoid inter-origin gaps too large to be fully copied. Fundamental principles of eukaryotic origin firing are known. We here discuss advances in understanding the regulation of origin firing to control firing time. Work with yeasts suggests that eukaryotes utilise distinct molecular pathways to determine firing time of distinct sets of origins, depending on the specific requirements of the genomic regions to be replicated. Although the exact nature of the timing control processes varies between eukaryotes, conserved aspects exist: (1) the first step of origin firing, pre-initiation complex (pre-IC formation), is the regulated step, (2) many regulation pathways control the firing kinase Dbf4-dependent kinase, (3) Rif1 is a conserved mediator of late origin firing and (4) competition between origins for limiting firing factors contributes to firing timing. Characterization of the molecular timing control pathways will enable us to manipulate them to address the biological role of replication timing, for example, in cell differentiation and genome instability. Full article
(This article belongs to the Special Issue DNA Replication Timing: Where, When, How and Why?)
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24 pages, 1780 KiB  
Review
On the Interplay of the DNA Replication Program and the Intra-S Phase Checkpoint Pathway
by Diletta Ciardo, Arach Goldar and Kathrin Marheineke
Genes 2019, 10(2), 94; https://doi.org/10.3390/genes10020094 - 29 Jan 2019
Cited by 28 | Viewed by 6469
Abstract
DNA replication in eukaryotes is achieved by the activation of multiple replication origins which needs to be precisely coordinated in space and time. This spatio-temporal replication program is regulated by many factors to maintain genome stability, which is frequently threatened through stresses of [...] Read more.
DNA replication in eukaryotes is achieved by the activation of multiple replication origins which needs to be precisely coordinated in space and time. This spatio-temporal replication program is regulated by many factors to maintain genome stability, which is frequently threatened through stresses of exogenous or endogenous origin. Intra-S phase checkpoints monitor the integrity of DNA synthesis and are activated when replication forks are stalled. Their activation leads to the stabilization of forks, to the delay of the replication program by the inhibition of late firing origins, and the delay of G2/M phase entry. In some cell cycles during early development these mechanisms are less efficient in order to allow rapid cell divisions. In this article, we will review our current knowledge of how the intra-S phase checkpoint regulates the replication program in budding yeast and metazoan models, including early embryos with rapid S phases. We sum up current models on how the checkpoint can inhibit origin firing in some genomic regions, but allow dormant origin activation in other regions. Finally, we discuss how numerical and theoretical models can be used to connect the multiple different actors into a global process and to extract general rules. Full article
(This article belongs to the Special Issue DNA Replication Timing: Where, When, How and Why?)
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