Where is dna replicated during the cell cycle

Similar interactions could also exist between histone acetylation and HATs, which are often located in complexes that contain acetyl-histone readers, such as bromodomain proteins Dhalluin et al. Indeed, recent work in human cell lines seems to support this model. Alabert et al. This implies that significant amounts of certain PTMs on nascent chromatin can originate from the old recycled histones Alabert et al. In further support of the model, they also find the PRC2 complex is present in both nascent and mature chromatin, consistent with rapid recruitment by recycled parental histones carrying H3K27Me3.

However, a very different model for inheritance of the epigenetic mark through S-phase was proposed by a study of early stage Drosophila embryos Petruk et al. Petruk et al.

They reasoned that the true epigenetic modifications should be re-established shortly after DNA replication. In this assay, proteins or histone PTMs that are within 30—40 nm of replication forks containing PCNA generate a fluorescent signal, with a sensitivity that allows visualization of single molecule interactions in vivo Soderberg et al.

This suggests that it is the PTM writers that remain associated with nascent chromatin during replication which must act to re-establish PTMs later. Thus, it seems the chromatin binding of the PTM writers rather than the PTMs themselves may serve as a true, inherited epigenetic mark.

Although surprising, this work is consistent with a previous study showing that Polycomb remains bound to replicating chromatin in vitro Francis et al. Self-association and oligomerization may be another manner in which PTM writers can be maintained in the absence of a recruiting PTM Lo et al. However, it remains unclear in the Drosophila embryo whether the PTM writers remain associated with the same specific locations on DNA before and after replication fork passage.

These seemingly conflicting observations of Alabert et al. For example, in the Drosophila embryo it seems relatively few PTMs may have already been established on the mature nucleosomes at the stage of development under study. Indeed the authors show there is little to no H3K27Me3 at the cellular blastoderm stage before gastrulation.

Thus perhaps when there are lower levels of established PTMs, they can be preceded by the binding of the histone modifiers in S-phase Petruk et al. In contrast, the adult human cells have already heavily established PTMs in the chromatin prior to passage of the replication fork, and thus recycling histones containing PTMs allows them to more readily be used as a template to recruit modifying enzymes and re-establish the necessary chromatin modifications. A new study using early C. In contrast to the results in Drosophila , Gaydos et al.

A chromosome inherited with the H3K27Me3 mark already established, retains it during early embryonic divisions exhibiting only the expected level of passive dilution due to new histone incorporation.

While chromosomes in the exact same embryo- inherited without the H3K27Me3 mark already established, cannot establish it de novo until later in development. Taken together, the studies of Petruk et al. Perhaps flies use chromatin-bound PTM writers to carry the epigenetic information through early embryonic cell divisions, while worms use the PTM itself?

An organism specific answer to the epigenetic inheritance question seems a bit unsatisfying, especially as all the ingredients, the PTMs, the readers, the writers and the S-phase machinery are so well conserved.

Hopefully future studies will be able to reveal an underlying unifying concept to explain what is the true inherited epigenetic mark. To ensure the fidelity of separating identical genetic information into two daughter cells, chromatin undergoes dramatic compaction during the cell cycle into mitotic chromosomes.

Mitotic chromosomes are easily recognizable based on their morphology, however, the details of their three-dimensional structure have remained enigmatic. Recent use of advanced Chromosome Conformation Capture methods such as 5C and Hi-C in human cell lines performed at timepoints across the cell cycle, have revealed that mitotic chromosomes exhibit a common structure shared in multiple cell types Naumova et al. Mitotic chromosomes appear to be organized as a linear array of chromatin loops of variable size, which are then tightly compressed together longitudinally.

The common structure of mitotic chromosomes seems striking, given the cell type-specific subdomains and features of interphase chromatin structure, such as TADs Pope et al. This suggests that some cell-type specific chromatin architecture is lost during mitosis and higher-order chromatin structures form de novo after mitosis.

Accompanying this dramatic chromatin compaction is the alteration of chromatin-based activities, such as the cessation of transcription Martinez-Balbas et al. This is thought to be accomplished in part, by the inhibition of transcription factor binding to the mitotic chromatin. For example, the large C2H2 zinc finger transcription factor family becomes phosphorylated at the conserved linker region during mitosis, which leads to dissociation from mitotic chromatin Dovat et al.

Alternatively for specific transcription factors that remain bound to the mitotic chromosome, such as FoxA1 and GATA1, their co-activators can be excluded from mitotic chromatin. DNase sensitivity has been used to probe chromatin accessibility during different stages of the cell cycle. Somewhat surprisingly and in contrast to the Hi-C data mentioned previously, DNase sensitivity is widely preserved from interphase to mitosis Hsiung et al.

During interphase, DNAse sensitivity generally corresponds to transcription factor binding sites and active gene proximal promoters. While in mitosis, gene expression ceases, higher order chromatin domains are lost and many transcription factors are ejected. So why and how are most DNase sensitive regions maintained during mitosis? First to be precise, there are a few expected alterations to accessibility in mitosis.

For example, distal regulatory elements that bind transcription factors are somewhat more likely to lose accessibility during mitosis compared to gene proximal promoters. Second, chromatin modifications and some chromatin modifiers are retained on the mitotic chromosomes and can help to preserve local chromatin structure, even if higher order structures are disrupted, as suggested by the Hi-C data. For example, the trithorax protein MLL maintains its chromatin association during mitosis, and loss of MLL impairs the rapid reactivation of MLL target genes after mitotic exit Blobel et al.

This process is reminiscent of the mitotic bookmarking described above, and suggests that retention of a few key chromatin modifiers during mitosis may be all that is needed to transmit gene expression information and maintain cell fate through mitosis. What are the histone PTMs involved in compacting the chromatin at mitosis? The best-documented mitotic chromatin mark is phosphorylation of the H3 N-terminal tails. Four major residues of H3 are phosphorylated during mitosis, T3, S10, T11, S28, in a manner conserved from yeasts to humans Rossetto et al.

Aurora B is the major kinase responsible for these phosphorylations, which can be counteracted by the Protein Phosphatase 1 PP1. Insufficient H3 phosphorylation leads to abnormal chromosome condensation and segregation, which is due to impaired recruitment of Condensin I complexes Adams et al. The Condensin complex is the major effector of chromosome condensation during mitosis. In the presence of type I topoisomerases, Condensins progressively wind and fold the chromatin fiber into supercoils, which compact to form the mitotic chromosome Hirano, ; Thadani et al.

Importantly though, phosphorylation of H3 does more than simply recruit Condensins, it can also modulate the binding of repressive chromatin proteins to mitotic chromosomes. For example, H3K9 the residue adjacent to H3S10 can be methylated and its trimethylation recruits the HP1 reader to form heterochromatin. H4K16Ac inhibits chromatin compaction, and consistent with a role in opening chromatin, its levels normally peak during S phase Shogren-Knaak et al. H4K20Me is also thought to contribute to chromosome compaction in early M phase by binding specific components of the Condensin II complex Liu et al.

Condensin II binds to interphase chromatin and is thought to mediate early phases of chromatin compaction, well before Condensin I. Altogether this suggests a two-step model for chromatin modifications to promote chromosome compaction at mitosis.

This then cooperates with Aurora B triggered H3 phosphorylation to eject H3K9-and possibly H3K27 -bound protein complexes and recruit Condensin I during early metaphase for further compaction Ono et al. In this manner, the compaction of the chromatin at mitosis and the ejection of certain chromatin bound factors are directly coupled. While chromatin impacts cell cycle events like origin firing and chromosome segregation at mitosis, the cell cycle machinery also impacts chromatin by regulating the histone modifiers.

The activity of certain histone modifiers fluctuates in a cell cycle-dependent manner. The dynamic regulation of PR-Set7 is in part due to its proteolytic degradation during S-phase. In addition to H4K20 associated modifiers, cell cycle dependent regulation of other PTM writers has also been reported.

EZH2, the mammalian homolog of Enhancer of zeste, E z in Drosophila , is the major methyltransferase for H3 Lysine 27 and plays a crucial role in differentiation gene silencing through interaction with the Polycomb Repressive Complex 2 PRC2; Cao et al.

This phosphorylation reinforces differentiation-associated gene silencing, such as silencing of HOX genes and SOX family members, and is thought to maintain stem cell identity Chen et al. Thus, the cell cycle regulation of EZH2 can have both positive and negative outcomes on stem cell identity and differentiation. How these outcomes are balanced in actively proliferating cells remains unclear.

Although there is plentiful data suggesting that EZH2 is important for normal cell proliferation and maintaining stem cell identity, whether part or all of these functions occur through PRC2-dependent gene silencing or another role of EZH2 is not known. To fully understand how EZH2 coordinates with the cell cycle machinery to promote proliferation and maintain stem cell identity, further investigations will be required. These specific examples of the cell cycle machinery impacting chromatin modifiers are likely to be only the tip of the iceberg.

In addition the myriad of other cell cycle kinases, phosphatases, ubiquitin ligases and their targets are only recently being uncovered on a proteomic scale Bernal et al. Such large-scale approaches are likely to reveal new connections between the cell cycle machinery and chromatin regulators, which lie at the core of coordinating gene expression, with genome duplication and segregation.

Chromatin is not organized randomly within the nucleus during interphase, and microscopic observations of mammalian nuclei revealed that condensed chromatin is localized preferentially in the nuclear periphery, interrupted by stretches of less condensed chromatin at the nuclear pore complexes NPCs. Consistent with this idea, active genes in yeast have been found to be localized at the Nuclear pore basket, including housekeeping genes and inducible genes that become re-located to the NPCs upon activation Dieppois and Stutz, ; Burns and Wente, Gene recruitment to these regions is dependent upon specific sequences termed GRS I and II present in the inducible gene promoters Ahmed et al.

In the special, amplified polytene chromosomes of Drosophila salivary glands, Nup98 and Nup50 can be observed bound to decondensed chromatin and sites of active transcription microscopically. Nup98 and another Nup, Sec13, are localized to transcribed genes prior to the initiation of transcription, and an RNAi knockdown of Sec13 or Nup98 reduces transcription and RNA polymerase II recruitment, demonstrating functional roles for this binding Capelson et al.

However, the same Nups can also bind different set of genes when located in the pore vs. Thus, in metazoans actively transcribed genes bound by Nups are more likely to be found in the nucleoplasm while NPC binding is correlated with lower gene expression levels. Transcriptional memory is a phenomenon whereby a recently expressed and shut-off gene is transcriptionally re-activated faster after exposure to the same stimulus for second time, allowing cells to respond quickly to environmental changes.

This phenomenon can last through several cell divisions, demonstrating epigenetic inheritance Brickner, Transcriptional memory is conserved in mammals and also requires Nucleoporin binding. In both cases, at yeast and human genes, transcriptional memory is associated with increased dimethylation of H3K4 H3K4Me2 in the promoters, a mark which is dependent upon the interaction with the Nups Light et al. However, H3K4 methylation is apparently not necessary for transcriptional memory, as deletion of the responsible Set1 methylase in yeast does not prevent transcriptional memory at Gal1 and Gal10 loci Kundu et al.

Overall, yeast and mammalian cells seem to share a common mechanism regarding transcriptional memory, which requires Nucleoporin binding, but in yeast this interaction occurs at the NPCs, while in mammals it occurs in the nucleoplasm.

The mammalian ortholog of Nup Nup interacts with the HDAC4, also involved in transcriptional repression, revealing a conserved Nucleoporin function in silencing Kehat et al. The localization of chromatin to the nuclear periphery, away from pores is suggested to be transcriptionally repressive in yeast and mammals Andrulis et al.

Using this mechanism to silence gene expression involves chromatin movement from the nucleoplasm to the nuclear periphery. Chromosomes maintain certain positions in interphase nuclei Chubb et al. This may be because the nuclear envelope-chromatin interactions need to be disrupted and re-established, an event driven by the open mitosis in mammalian cells.

Importantly, this also suggests post-mitotic cells can use this repressive mechanism to permanently silence genes, and suggests a manner by which forcing cell cycle re-entry of postmitotic cells may promote chromatin re-localization and create a state permissive for cell de-differentiation Nicolay et al. Heterochromatin tethering along the nuclear periphery is mediated by lamins, nuclear cytoskeleton filaments, that connect chromatin to the inner nuclear membrane of the nuclear envelope Dechat et al.

Lamin-associated aomains LADs of the mammalian genome contain a relatively low number of genes and exhibit a repressed chromatin state Guelen et al. LADs have been shown in a number of studies to modulate gene expression, and repositioning genes to a LAD is sufficient to mediate repression Kosak et al. A detailed analysis of LAD positioning during the cell cycle was performed using a modified Dam-ID approach, to permanently mark chromatin regions that associate with nuclear lamina, and track their position even after detachment and through the cell cycle Kind et al.

The study revealed that in a human cell line, LADs are generally found in nuclear periphery during interphase and are enriched for the H3K9Me2 PTM, associated with gene silencing. However, after mitosis the LADs from the prior interphase do not re-establish a peripheral localization in the nucleus, instead they become distributed stochastically between the nucleoplasm and nuclear periphery. This profound and surprising result raises the question of how such stochastic changes in chromatin dynamics during each cell cycle, and presumably gene expression, can possibly be reconciled with seemingly organized and predictable changes in cell fate during development.

One possibility is that LADs may be primarily used to modulate gene expression in postmitotic cells, although studies performed in proliferating fibroblasts suggest this may not be the case Reddy et al. Importantly, new single-cell based assays are revealing a surprising amount of stochastic variation in individual cell decisions of quiescence vs. Does the inherent unpredictability of chromatin reorganization after mitosis possibly underlie this stochasticity?

This will be an interesting question to address in future research. This involves the disassembly of NPCs, lamin depolymerization, and incorporation of nuclear envelope membranes into the endoplasmic reticulum ER reviewed in Guttinger et al. When these residues are mutated to sites that cannot be phosphorylated, NPC disassembly is delayed, suggesting that Nup98 phosphorylation is an initial and critical step in NPC disassembly at mitosis.

When mitosis is complete, the nuclear envelope must be re-assembled. NPCs are initially re-assembled through interactions with chromatin, followed by association of membranes to form the closed nuclear envelope. Subsequently, interaction of Nup— with the transmembrane Nup Pom allows the recruitment of membrane vesicles and also mediates interactions with other Nups Nup93— How are enough NPCs produced during interphase to be equally divided between daughter cells at the next mitosis?

In contrast to post-mitotic NPC re-assembly, where the inactivation of mitotic Cdk1 and de-phosphorylation of Nups and other nuclear envelope proteins is required, NPC production during interphase is positively regulated by Cdk activity, in particular Cdk1 and Cdk2 Maeshima et al.

Interphase NPC assembly initiates with the entrance of the transmembrane Pom Nup to the nucleus, and its localization to the inner nuclear membrane Funakoshi et al. The Nup— complex is subsequently recruited, but the detailed sequence for interphase NPC assembly remains unclear Capelson et al. Apart from the assembly of NPCs, their distribution in the nuclear membrane during cell cycle progression changes as well.

As NPCs and Lamins both bind chromatin and affect gene expression, the changes in distribution of the nuclear envelope proteins could potentially affect gene expression throughout the cell cycle Figure 1. How is chromatin tethered to the nuclear pores or nuclear lamina properly replicated during S-phase?

The anchoring of chromatin to NPCs turns out to have both positive and negative impacts on genome integrity during replication. While it is not exactly clear why movement to the NPCs facilitates repair, it has been proposed that the nuclear periphery may provide a special permissive environment for additional DSB repair pathways beyond homologous recombination and non-homologous end joining to repair persistent DSBs Oza et al. While recruitment to pores can promote DNA repair, paradoxically, the anchoring of actively transcribed genes to NPCs can also be a source of replication stress.

It is thought that as the DNA replication fork proceeds, it will eventually meet the NPC- tethered region actively transcribing genes. The inflexibility of tethered DNA can become a source of tension as the unwinding of DNA occurs during replication fork progression Branzei and Foiani, , and the tension generated between an actively transcribed region tethered to the NPC and the approaching replication fork is somehow released by the activity of the DNA damage checkpoint kinases and their associated complexes Bermejo et al.

When the checkpoint response is inhibited, replication forks collapse and firing of dormant replication origins occurs Bermejo et al. It remains unclear whether a similar checkpoint mechanism is applied upon replication of transcribed genes that are not tethered to the NPC, for example those bound to other immobile nuclear structures.

Apart from chromatin anchoring, Nups facilitate the maintenance of genome integrity also by affecting the nuclear transport of DNA damage repair proteins required during the cell cycle.

When Tpr is depleted, the nuclear export of p53 becomes compromised, resulting in nuclear accumulation of p53 and activation of downstream target genes such as p21 leading to premature senescence David-Watine, Cellular differentiation and proliferation must be intimately coordinated for proper development and tissue homeostasis.

Stem cells pose a special case in this regard, as they must proliferate when needed, yet retain their undifferentiated status Fuchs, ; Lange and Calegari, ; Li and Clevers, The cell cycle of pluripotent embryonic stem ES is reminiscent of that in early embryos, characterized by very short gap phases. Upon differentiation G1 phase becomes longer, more similar to adult somatic cells Singh and Dalton, ; Calder et al.

When undifferentiated human ES stem cells are isolated in different phases of the cell cycle, their propensity for spontaneous differentiation in culture varies. G1-phase cells exhibit a high rate of spontaneous differentiation, while S, and G2 -phase cells exhibit reduced spontaneous differentiation Sela et al.

Interestingly, the propensity of G1 cells to differentiate, is reduced when co-cultured with S and G2 phase cells in direct contact, suggesting cell cycle-dependent cell to cell signaling may be partly responsible for this effect. In vivo , the propensity for embryonic neural stem cells to self-renew vs. What are the molecular mechanisms connecting cell fate acquisition with prolonged G1?

Human ES cells with hypo- or unphosphorylated RB exhibit the highest propensity to spontaneously differentiate, suggesting even a transient quiescence may consequently promote differentiation Sela et al.

Whether these differences may be organism or cell-line specific remains to be determined, but multiple lines of evidence support a relationship between cell cycle changes and cell fate acquisition in human ES cells Calder et al. While the capacity for ES cells to differentiate may be established during quiescence, there is evidence that in adult cells differentiation is actively inhibited during quiescence through the transcriptional repressor Hes1 Sang et al.

Inhibition of differentiation during quiescence is critical for adult stem cells, which can spend prolonged periods in an arrested state, yet must retain their stem cell capacity Fuchs and Chen, This suggests there will be distinct mechanisms that link the cell cycle with cell fate acquisition in adult vs. ES cells. A view of the molecular signaling mechanisms that coordinate cell fate decisions with the core cell cycle machinery in ES cells is just beginning to emerge.

The ability to monitor differentiation and cell cycle dynamics in real-time, at the single-cell level, has been made possible by the use of the Fluorescent Ubiquitylation-based Cell-Cycle Indicator FUCCI system Sakaue-Sawano et al. The FUCCI system facilitated the studies of Pauklin and Vallier by allowing them to use flow cytometry to precisely sort stem cells based upon their cell cycle phase.

Using a similar approach, also in human ES cells, Singh et al. They find that genes expressed specifically during G1 are heavily enriched for roles in development and cell-fate commitment and that these changes in gene expression are dependent upon cell cycle status Singh et al.

To determine how this cell cycle-dependent gene expression is regulated, they examined global chromatin changes during the cell cycle and unexpectedly found that the cytosine modification 5-hydroxymethylcytosine 5hmC is increased during late G1, followed by a sharp decline in S-phase, and re-established during G2. Interestingly, the loss of methylation during S phase may be greater than that expected by simple passive loss through the incorporation of new unmodified nucleotides during DNA replication.

If this is the case, there may be cell cycle regulated active de-methylation during S-phase in stem cells. In contrast to the better-known repressive cytosine methylation 5mC, 5hmC is instead associated with active promoters, increased gene expression and genes poised for rapid expression Jin et al.

Bivalent domains have been suggested to simultaneously prevent premature expression of differentiation genes in ES cells via the repressive H3K27me3 mark, yet simultaneously keep them poised for rapid expression upon differentiation via the H3K4me3 mark, although this model is controversial Vastenhouw and Schier, ; Voigt et al. The work of Singh now adds an extra layer to the puzzle by demonstrating an additional chromatin modification that appears to be under the control of the cell cycle machinery.

It remains unknown how and why 5hmC is increased during the G1 phase and re-established at G2, or perhaps more importantly how and why de-methylation occurs during S phase. It will be important to investigate the molecular mechanisms linking genome methylation with the cell cycle machinery in stem cells. While it has been discussed for over two decades that the response of cells to differentiation cues seems to be affected by their cell cycle status, we are just now beginning to decipher the specific mechanisms linking the cell cycle to the chromatin state and the acquisition of cell fate.

While differentiation and lineage restriction of pluripotent cells seems to be increased during the G1-phase of the cell cycle, multiple lines of evidence suggest the acquisition of pluripotency or potential for nuclear reprogramming is increased during mitosis Egli et al. An increase in nuclear reprogramming efficiency at mitosis may seem surprising at first glance, since the use of quiescent G0 nuclei was suggested to be essential to the success of the most famous example of mammalian cloning, Dolly the ewe Campbell et al.

However, subsequent examples of mammalian cloning demonstrated that actively dividing cells could be efficiently used for donor nuclei Cibelli et al.

More recent cell reprogramming experiments carried out through cell-fusion of differentiated cells with mouse ES cells to form heterokaryons, suggested that successful reprogramming of chromatin actually requires activation of DNA synthesis within the first 24 h of cell fusion Tsubouchi et al. In this case, DNA synthesis was suggested to facilitate nuclear reprogramming by passively diluting existing DNA methylation marks.

But there are additional observations suggesting active cell cycling and more specifically mitosis is advantageous for nuclear reprogramming.

In studies using somatic nuclear transfer in Xenopus , the use of nuclei that have recently undergone mitosis was shown to increase origin accessibility in the oocyte, which poises the donor nuclei for the rapid S-phase entry and progression required during early Xenopus development Lemaitre et al.

Later work by Ganier et al. Permeabilized mouse embryonic fibroblasts exposed to mitotic egg extract, but not interphase extract, exhibit decreased histone modifications such as H3K9, H3K4, and H4K20 di- and trimethylation and increased expression of pluripotency-associated genes.

When somatic cell nuclear transfer was subsequently performed with the mouse fibroblast nuclei exposed to the mitotic extract, a fourfold increase in reprogramming efficiency was observed Ganier et al. This ability of a mitotic egg extract to facilitate mammalian nuclear reprogramming was suggested at least in part, to be due to the extract promoting M-phase entry in the fibroblast nuclei.

Indeed, mitotic figures and histone marks associated with mitosis were observed in the fibroblast nuclei exposed to the extract. How exactly does the mitotic status of a donor nucleus facilitate cell fate reprogramming? Halley-Stott et al. They find, consistent with the reprogramming studies of others Egli et al. This mitotic advantage for chromatin reprogramming to pluripotency can be observed in donor nuclei from different cell types and cannot be explained simply by the increased nuclear permeability at mitosis.

The authors systematically removed different components from the mitotic chromatin to identify the molecular basis of this advantage.

In sum, mitotic advantage appears to require nucleosomes, but cannot be explained by histone acetylation, phosphorylation, or methylation. Rather their data suggest that the loss of ubiquitination on histones H2A and H2B during mitosis Joo et al. Future studies will therefore be needed to identify the additional factors involved in mitotic advantage. The work of Halley-Stott et al. They suggest the removal of most transcription factors from mitotic chromosomes actually increases their accessibility to reprogramming factors, which allows for rapid induction upon exit from mitosis as soon as transcription resumes Halley-Stott et al.

Given the stochasticity inherent in the cellular reprogramming progress Hanna et al. Extensive connections between the cell cycle machinery and chromatin clearly exist, which impact gene expression and thus, cell fate decisions in important ways. While the use of asynchronous cell culture or mixed lineage tissues has sometimes hampered our ability to see these connections, new tools such as Chromatin Conformation Capture, the FUCCI system, the PLA and modified versions of DamID, are being used in ways that allow detailed views of the cell cycle, chromatin state and cell fate acquisition that were previously impossible.

But several key questions remain unresolved. For example, does the gene expression profile of a cell, and thus cell fate, control important facets of the cell cycle such as origin choice and DNA replication timing?

Or does the cell cycle status of a cell instead determine its gene expression possibilities and therefore limit choices in cell fate? If the latter is true, how can cell fate be so robustly maintained in some instances of regeneration or in cases of cell cycle disruption during development?

As we learn more about the truly plastic nature of cell fate, we expect to find that the cell cycle influences the probability of acquiring certain cell fate programs, but that multiple cell cycle and cell fate states can be compatible under specific conditions.

Future work will continue to uncover new molecular connections between the cell cycle machinery and developmental signaling pathways, to help us finally understand how the cell cycle impacts cell fate. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abbas, T. Cell 40, 9— Adams, R. Essential roles of Drosophila inner centromere protein INCENP and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation.

Cell Biol. Aggarwal, B. Chromatin regulates origin activity in Drosophila follicle cells. Nature , — Ahmed, S. DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery. Alabert, C. Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Chromatin replication and epigenome maintenance.

Andrulis, E. Perinuclear localization of chromatin facilitates transcriptional silencing. Aragon, L. Condensin, cohesin and the control of chromatin states. Arai, Y. Neural stem and progenitor cells shorten S-phase on commitment to neuron production.

Bannister, A. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Berger, S. An operational definition of epigenetics. Genes Dev. Bermejo, R. The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores. Cell , — Bernal, M.

Proteome-wide search for PP2A substrates in fission yeast. Proteomics 14, — Blobel, G. Gene gating: a hypothesis. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Cell 36, — Boos, D. Identification of a heteromeric complex that promotes DNA replication origin firing in human cells.

Science , — Bostick, M. Bracken, A. EMBO J. Branzei, D. Maintaining genome stability at the replication fork. Brickner, J. Transcriptional memory at the nuclear periphery. Buchwalter, A. Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics. Cell 25, — Burns, L.

From hypothesis to mechanism: uncovering nuclear pore complex links to gene expression. Cabal, G. SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelope. Cadoret, J. Genome-wide studies highlight indirect links between human replication origins and gene regulation. Calder, A. Lengthened g1 phase indicates differentiation status in human embryonic stem cells. Stem Cells Dev. Campbell, K. Cell cycle co-ordination in embryo cloning by nuclear transfer.

Sheep cloned by nuclear transfer from a cultured cell line. Nature , 64— Cao, R. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Capelson, M. Nuclear pore complexes: guardians of the nuclear genome.

Spring Harb. Caravaca, J. Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Cayrou, C. Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features.

Genome Res. Centore, R. CRL4 Cdt2 -mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Cell 40, 22— J Cell Sci , — McFarlane, R.

The many facets of the Tim-Tipin protein families' roles in chromosome biology. Cell Cycle 9 , — Nasmyth, K. Cohesin: its roles and mechanisms. Annu Rev Genet 43 , — Noguchi, E. Swi1 and Swi3 are components of a replication fork protection complex in fission yeast. Mol Cell Biol 24 , — Nyberg, K. Annu Rev Genet 36 , — Paulsen, R. The ATR pathway: fine-tuning the fork. Uhlmann, F. A matter of choice: the establishment of sister chromatid cohesion. EMBO reports 10 , Eukaryotes and Cell Cycle.

Cell Differentiation and Tissue. Cell Division and Cancer. Cytokinesis Mechanisms in Yeast. Recovering a Stalled Replication Fork. Aging and Cell Division. Germ Cells and Epigenetics. Citation: Noguchi, E. Nature Education 3 9 The replication fork is more than just a means for DNA duplication. It is connected to a checkpoint system that keeps the genome intact and prevents cancer.

Aa Aa Aa. Figure 1: Obstacles on DNA that generate stalled replication forks. Figure Detail. Figure 2: Checkpoint responses. Figure 3: Fork protection. Stabilizing replisome components at the replication fork when the fork stalls, so that the fork can re-start after the problems are solved. Preventing fork breakage.

If the fork is broken, fork protectors may be required to re-assemble replisome components. Protecting the replication forks in a configuration that is recognized by replication checkpoint proteins Figure 2. References and Recommended Reading Abraham, R. Article History Close. Share Cancel. Revoke Cancel. Keywords Keywords for this Article. Save Cancel. Flag Inappropriate The Content is: Objectionable.

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Or Browse Visually. Student Voices. Creature Cast. Simply Science. Green Screen. Green Science. Bio 2. The Success Code. Why Science Matters. The Beyond. Plant ChemCast. Hubscher, U. Eukaryotic DNA polymerases. Annual Review of Biochemistry 71 — doi Katou, Y. S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature — doi Kouprina, N. Molecular and Cellular Biology 12 — Langston, L.

DNA replication: keep moving and don't mind the gap. Molecular Cell 23 — doi Menoyo, A. Cancer Research 61 — Merchant, A.

A lesion in the DNA replication initiation factor Mcm10 induces pausing of elongation forks through chromosomal replication origins in Saccharomyces cerevisiae. Molecular and Cellular Biology 17 — Miles, J. Moldovan, G. PCNA, the maestro of the replication fork. Cell — doi Moyer, S. Paulsen, R. A genome-wide siRNA screen reveals diverse cellular processes and pathways that mediate genome stability.

Molecular Cell 35 — doi Pizzagalli, A. DNA polymerase I gene of Saccharomyces cerevisiae: nucleotide sequence, mapping of a temperature-sensitive mutation, and protein homology with other DNA polymerases. Remus, D. Eukaryotes and Cell Cycle. Cell Differentiation and Tissue. Cell Division and Cancer. Cytokinesis Mechanisms in Yeast. Recovering a Stalled Replication Fork. Aging and Cell Division. Germ Cells and Epigenetics. Citation: Das-Bradoo, S. Nature Education 3 9 During DNA replication, the unwinding of strands leaves a single strand vulnerable.

How does the cell protect these strands from damage? Aa Aa Aa. Figure 1: The major replication events in a prokaryotic cell. A Nucleoside triphosphates serve as a substrate for DNA polymerase, according to the mechanism shown on the top strand. The Leading and Lagging Strands. These proteins are illustrated schematically in panel a of the figure below, but in reality, the fork is folded in three dimensions, producing a structure resembling that of the diagram in the inset b.

Triggering a Checkpoint. Other Roles for ATR. Stalled Forks. Nucleases can cleave stalled forks, causing double-strand breaks DSBs to form and activate ataxia-telangiectasia mutated ATM. References and Recommended Reading Alberts, B. Article History Close. Share Cancel. Revoke Cancel. Keywords Keywords for this Article. Save Cancel. Flag Inappropriate The Content is: Objectionable.

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