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DNA Replication Kinetics
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DNA Replication Kinetics

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

Deadline for manuscript submissions: closed (20 August 2022) | Viewed by 13902

Special Issue Editor

Prof. Dr. Nicholas R. Rhind

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Interests: DNA replication; replication initiation; single-molecule replication mapping; MCM loading; cell size contol; yeast

Special Issue Information

Dear Colleagues,

Reproducible patterns of DNA replication timing are seen across eukaryotes.  These replication timing patterns correlate with gene expression, chromatin structure, chromosome conformation and genome evolution, suggesting a deep interrelation between these fundamental nuclear processes.  Thus, understanding the regulation of replication timing is a major goal in the field of nuclear biology.  Nonetheless, neither the mechanisms that regulate replication timing, nor their biological implications are well understood.  Given the active work going on in the field, and the potential for new insight, this is an excellent time for a Special Issue dedicated to the topic.

In this Special Issue, we welcome original articles, new methods and reviews covering any aspect of DNA Replication Kinetics.  These include, but not limited to, regulation of the replication initiation, the mapping and regulation of replication origins, regulation of replication fork rate, developmental and checkpoint regulation of replication kinetics, replication timing of specific genomic loci (such as telomeres or rDNA), and other cellular processes that are coordinated with DNA replication timing.  We look forward to your contributions.

Prof. Dr. Nicholas R. Rhind
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Replication kinetics
  • Replication timing
  • Replication origin
  • Replication origin licensing
  • Replication origin activation
  • Replication initiation factors
  • Replication fork rate
  • Replication termination

Published Papers (6 papers)

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Research

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14 pages, 4564 KiB  
Article
Dbf4 Zn-Finger Motif Is Specifically Required for Stimulation of Ctf19-Activated Origins in Saccharomyces cerevisiae
by Meghan V. Petrie, Haiyang Zhang, Emily M. Arnold, Yan Gan and Oscar M. Aparicio
Genes 2022, 13(12), 2202; https://doi.org/10.3390/genes13122202 - 24 Nov 2022
Viewed by 1339
Abstract
Eukaryotic genomes are replicated in spatiotemporal patterns that are stereotypical for individual genomes and developmental profiles. In the model system Saccharomyces cerevisiae, two primary mechanisms determine the preferential activation of replication origins during early S phase, thereby largely defining the consequent replication [...] Read more.
Eukaryotic genomes are replicated in spatiotemporal patterns that are stereotypical for individual genomes and developmental profiles. In the model system Saccharomyces cerevisiae, two primary mechanisms determine the preferential activation of replication origins during early S phase, thereby largely defining the consequent replication profiles of these cells. Both mechanisms are thought to act through specific recruitment of a rate-limiting initiation factor, Dbf4-dependent kinase (DDK), to a subset of licensed replication origins. Fkh1/2 is responsible for stimulation of most early-firing origins, except for centromere (CEN)-proximal origins that recruit DDK via the kinetochore protein Ctf19, which is required for their early firing. The C-terminus of Dbf4 has been implicated in its recruitment to origins via both the Fkh1/2 and Ctf19 mechanisms. Here, we show that the Zn-finger motif within the C-terminus is specifically required for Dbf4 recruitment to CENs to stimulate CEN-proximal/Ctf19-dependent origins, whereas stimulation of origins via the Fkh1/2 pathway remains largely intact. These findings re-open the question of exactly how Fkh1/2 and DDK act together to stimulate replication origin initiation. Full article
(This article belongs to the Special Issue DNA Replication Kinetics)
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21 pages, 3727 KiB  
Article
Impact of Chromosomal Context on Origin Selection and the Replication Program
by Lilian Lanteri, Anthony Perrot, Diane Schausi-Tiffoche and Pei-Yun Jenny Wu
Genes 2022, 13(7), 1244; https://doi.org/10.3390/genes13071244 - 14 Jul 2022
Viewed by 1678
Abstract
Eukaryotic DNA replication is regulated by conserved mechanisms that bring about a spatial and temporal organization in which distinct genomic domains are copied at characteristic times during S phase. Although this replication program has been closely linked with genome architecture, we still do [...] Read more.
Eukaryotic DNA replication is regulated by conserved mechanisms that bring about a spatial and temporal organization in which distinct genomic domains are copied at characteristic times during S phase. Although this replication program has been closely linked with genome architecture, we still do not understand key aspects of how chromosomal context modulates the activity of replication origins. To address this question, we have exploited models that combine engineered genomic rearrangements with the unique replication programs of post-quiescence and pre-meiotic S phases. Our results demonstrate that large-scale inversions surprisingly do not affect cell proliferation and meiotic progression, despite inducing a restructuring of replication domains on each rearranged chromosome. Remarkably, these alterations in the organization of DNA replication are entirely due to changes in the positions of existing origins along the chromosome, as their efficiencies remain virtually unaffected genome wide. However, we identified striking alterations in origin firing proximal to the fusion points of each inversion, suggesting that the immediate chromosomal neighborhood of an origin is a crucial determinant of its activity. Interestingly, the impact of genome reorganization on replication initiation is highly comparable in the post-quiescent and pre-meiotic S phases, despite the differences in DNA metabolism in these two physiological states. Our findings therefore shed new light on how origin selection and the replication program are governed by chromosomal architecture. Full article
(This article belongs to the Special Issue DNA Replication Kinetics)
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13 pages, 11899 KiB  
Article
Cell-Cycle–Dependent Chromatin Dynamics at Replication Origins
by Yulong Li, Alexander J. Hartemink and David M. MacAlpine
Genes 2021, 12(12), 1998; https://doi.org/10.3390/genes12121998 - 16 Dec 2021
Cited by 3 | Viewed by 2484
Abstract
Origins of DNA replication are specified by the ordered recruitment of replication factors in a cell-cycle–dependent manner. The assembly of the pre-replicative complex in G1 and the pre-initiation complex prior to activation in S phase are well characterized; however, the interplay between the [...] Read more.
Origins of DNA replication are specified by the ordered recruitment of replication factors in a cell-cycle–dependent manner. The assembly of the pre-replicative complex in G1 and the pre-initiation complex prior to activation in S phase are well characterized; however, the interplay between the assembly of these complexes and the local chromatin environment is less well understood. To investigate the dynamic changes in chromatin organization at and surrounding replication origins, we used micrococcal nuclease (MNase) to generate genome-wide chromatin occupancy profiles of nucleosomes, transcription factors, and replication proteins through consecutive cell cycles in Saccharomyces cerevisiae. During each G1 phase of two consecutive cell cycles, we observed the downstream repositioning of the origin-proximal +1 nucleosome and an increase in protected DNA fragments spanning the ARS consensus sequence (ACS) indicative of pre-RC assembly. We also found that the strongest correlation between chromatin occupancy at the ACS and origin efficiency occurred in early S phase, consistent with the rate-limiting formation of the Cdc45–Mcm2-7–GINS (CMG) complex being a determinant of origin activity. Finally, we observed nucleosome disruption and disorganization emanating from replication origins and traveling with the elongating replication forks across the genome in S phase, likely reflecting the disassembly and assembly of chromatin ahead of and behind the replication fork, respectively. These results provide insights into cell-cycle–regulated chromatin dynamics and how they relate to the regulation of origin activity. Full article
(This article belongs to the Special Issue DNA Replication Kinetics)
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17 pages, 53281 KiB  
Article
Organization of DNA Replication Origin Firing in Xenopus Egg Extracts: The Role of Intra-S Checkpoint
by Diletta Ciardo, Olivier Haccard, Hemalatha Narassimprakash, Jean-Michel Arbona, Olivier Hyrien, Benjamin Audit, Kathrin Marheineke and Arach Goldar
Genes 2021, 12(8), 1224; https://doi.org/10.3390/genes12081224 - 09 Aug 2021
Cited by 3 | Viewed by 2354
Abstract
During cell division, the duplication of the genome starts at multiple positions called replication origins. Origin firing requires the interaction of rate-limiting factors with potential origins during the S(ynthesis)-phase of the cell cycle. Origins fire as synchronous clusters which is proposed to be [...] Read more.
During cell division, the duplication of the genome starts at multiple positions called replication origins. Origin firing requires the interaction of rate-limiting factors with potential origins during the S(ynthesis)-phase of the cell cycle. Origins fire as synchronous clusters which is proposed to be regulated by the intra-S checkpoint. By modelling the unchallenged, the checkpoint-inhibited and the checkpoint protein Chk1 over-expressed replication pattern of single DNA molecules from Xenopus sperm chromatin replicated in egg extracts, we demonstrate that the quantitative modelling of data requires: (1) a segmentation of the genome into regions of low and high probability of origin firing; (2) that regions with high probability of origin firing escape intra-S checkpoint regulation and (3) the variability of the rate of DNA synthesis close to replication forks is a necessary ingredient that should be taken in to account in order to describe the dynamic of replication origin firing. This model implies that the observed origin clustering emerges from the apparent synchrony of origin firing in regions with high probability of origin firing and challenge the assumption that the intra-S checkpoint is the main regulator of origin clustering. Full article
(This article belongs to the Special Issue DNA Replication Kinetics)
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Review

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14 pages, 2263 KiB  
Review
Rif1-Dependent Control of Replication Timing
by Logan Richards, Souradip Das and Jared T. Nordman
Genes 2022, 13(3), 550; https://doi.org/10.3390/genes13030550 - 20 Mar 2022
Cited by 12 | Viewed by 3254
Abstract
Successful duplication of the genome requires the accurate replication of billions of base pairs of DNA within a relatively short time frame. Failure to accurately replicate the genome results in genomic instability and a host of diseases. To faithfully and rapidly replicate the [...] Read more.
Successful duplication of the genome requires the accurate replication of billions of base pairs of DNA within a relatively short time frame. Failure to accurately replicate the genome results in genomic instability and a host of diseases. To faithfully and rapidly replicate the genome, DNA replication must be tightly regulated and coordinated with many other nuclear processes. These regulations, however, must also be flexible as replication kinetics can change through development and differentiation. Exactly how DNA replication is regulated and how this regulation changes through development is an active field of research. One aspect of genome duplication where much remains to be discovered is replication timing (RT), which dictates when each segment of the genome is replicated during S phase. All organisms display some level of RT, yet the precise mechanisms that govern RT remain are not fully understood. The study of Rif1, a protein that actively regulates RT from yeast to humans, provides a key to unlock the underlying molecular mechanisms controlling RT. The paradigm for Rif1 function is to delay helicase activation within certain regions of the genome, causing these regions to replicate late in S phase. Many questions, however, remain about the intricacies of Rif1 function. Here, we review the current models for the activity of Rif1 with the goal of trying to understand how Rif1 functions to establish the RT program. Full article
(This article belongs to the Special Issue DNA Replication Kinetics)
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6 pages, 233 KiB  
Review
f = m*a: A Framework for Investigating the Regulation of Replication Timing
by Nicholas Rhind
Genes 2022, 13(2), 249; https://doi.org/10.3390/genes13020249 - 28 Jan 2022
Cited by 1 | Viewed by 1737
Abstract
Stochastic models of replication timing posit that origin firing timing is regulated by origin firing probability, with early-firing origins having a high probability of firing and late-firing origins having a lower probability. However, they offer no insight into why one origin should have [...] Read more.
Stochastic models of replication timing posit that origin firing timing is regulated by origin firing probability, with early-firing origins having a high probability of firing and late-firing origins having a lower probability. However, they offer no insight into why one origin should have a higher firing probability than another. Here, a simple framework is suggested for how to approach the question by noting that the firing probability (f) must be the product of the stoichiometry of the MCM replicative helicase loaded at the origin (m) and the probability with which that MCM is activated (a). This framework emphasizes that mechanistic understanding of replication timing must focus on MCM loading and activation and can be simplified to the equation f = m*a. Full article
(This article belongs to the Special Issue DNA Replication Kinetics)
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