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2016 Action item: Rewrite cell textbooks re S-phase?

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From ScienceDaily:

All science students learn how human cell division takes place. The copying or replication of the genome, the cell’s DNA, has until now been believed only to take place during the so-called S-phase in the cell cycle. The new results show that this is not the case, because some regions of the genome are copied only after the cell enters the next crucial phase in the cell cycle called mitosis.

“It has radically altered our views and requires that the textbook view of the human cell cycle be revised,” says Professor Ian Hickson, Director of the Centre for Chromosome Stability and affiliated with the Center for Healthy Aging.

There is a cancer link:

This unusual pathway for copying of the DNA occurs at specific regions of the human genome called fragile sites, and during mitosis, chromosomes in these fragile areas have a tendency to break. The fragile sites are conserved across species and are frequently associated with undesirable genome rearrangements in connection with the development of cancer.

“We now know that these so-called ‘chromosome breaks’ are not actually broken, but instead comprise a region of DNA that is newly synthesized in mitosis. They appear broken because they are far less compacted than the rest of the chromosome,” adds Professor Hickson.

Cancer cells utilize this unusual form of DNA replication because one of the side effects of the genetic changes that cause cancer is so-called ‘replication stress’. More.

Meanwhile:

Evolution News and Views

See also: Fighting cancer with intelligent design:

In a sense, then, cancer arises through a Darwinian process of mutation and replication. Cancer is a multimutation feature that involves the devolution or destruction of genomic constraints on cell proliferation.

Now that we understand how cancer works, how do we fight it? We do so in much the same way we fight antibiotic resistance: by banking on the fact that there are limits to how quickly (or how much) cells can evolve. Dr. Audeh makes this exact point: … More.

Here’s the abstract of co-author Hickson’s paper:

Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis1. Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs)2, 3, 4, 5. CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS ‘expression’), particularly when cells have been exposed to replicative stress6. The MUS81–EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress7, 8, 9. Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN+) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach. (paywall) – Sheroy Minocherhomji, Songmin Ying, Victoria A. Bjerregaard, Sara Bursomanno, Aiste Aleliunaite, Wei Wu, Hocine W. Mankouri, Huahao Shen, Ying Liu, Ian D. Hickson. Replication stress activates DNA repair synthesis in mitosis. Nature, 2015; 528 (7581): 286 DOI: 10.1038/nature16139

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One Reply to “2016 Action item: Rewrite cell textbooks re S-phase?

  1. 1
    OLV says:

    Almost 3 years since this OP appeared here, there are no comments on such an interesting topic.

    How many readers of this website are really interested in scientific questions, at least at a non-professional level?

    How much has been found on this “mitosis”-related subject since this OP appeared here?

    OK, let’s take a look at a recent paper on a related topic:

    “Leader of the SAC: molecular mechanisms of Mps1/TTK regulation in mitosis”

    the regulation of Mps1 activity and its spatio-temporal distribution

    gaps in our understanding of these processes and propose future research avenues to address them.

    1. It’s got to be perfect: faithful chromosome segregation by attachment error correction and the spindle assembly checkpoint

    When a cell divides, the two resulting daughter cells each inherit an exact copy of its genetic content in order to maintain healthy cell function. Equal genome inheritance is driven by the mitotic spindle. Microtubules emanating from opposite poles of the spindle capture structures known as kinetochores on the two sister chromatids of chromosomes that were formed during the genome replication phase of the cell cycle. The sister chromatids separate only when every chromosome has achieved biorientation, a state in which one sister chromatid is attached to microtubules emanating from only one of the two poles while the other has attachments only to the other pole [1]. The result is the distribution of a complete copy of the genome towards opposite ends of the dividing cell, allowing fission to generate genetically identical daughters [2]. Compromised fidelity of chromosome segregation is implicated in a number of pathologies including cancer and in defects in embryonic development [36].

    2. All about that kinase: some Mps1 basics

    These findings are somewhat controversial, and it will be important to show that acute inhibition of Mps1 during interphase impairs these processes.

    3. Get busy: the orchestration of error correction and spindle assembly checkpoint by Mps1

    4. Start it up: molecular events leading to Mps1 activation

    It seems likely therefore that at least some nuclear Mps1 activity is generated before kinetochores are assembled but it is unknown if that activity comes from an NPC-localized pool or, for example, from a diffusible nucleoplasmic pool of Mps1. Such insight will have to await activity biosensors and mechanistic information on how Mps1 localizes to the NPC.

    5. Come together: how Mps1 binds kinetochores

    6. Under control: regulators of the interaction of Mps1 with kinetochores

    7. Let it go: a suggestion for a revised model of Mps1 release from kinetochores

    8. Keep ‘em separated: blocking access of Mps1 to its kinetochore substrates

    9. All together now: a temporal model for human MPS1 function in mitosis

    10. What else is there: outstanding questions

    Understanding its[*] role in the protection of genome stability is far from complete, however, and several key lacunas need to be filled.   [(*) the kinase Mps1]

    Very little is known about how and where this pool of Mps1 becomes activated.

    Several questions as to how this is achieved are as yet unanswered.

    How does dimerization of Mps1 occur and how does it affect the activation dynamics of the kinase?

    What are the steps leading to full activation of the kinase, and what are the roles of specific NTE and MR modifications?

    How exactly are Aurora B and ARHGEF17 involved in these initial Mps1–kinetochore interactions (figure 2C,D)?

    Have all contributing factors been identified?

    Is there, however, a role for such non-kinetochore Mps1 activity in the maintenance of a mitotic arrest after a full initial kinetochore-dependent SAC response has been mounted?

    Once Mps1 is displaced from kinetochores, how exactly does inactivation take place and what are the dynamics of it?

    where this residual Mps1 is binding and how much reduction of Mps1 levels is sufficient to tip the balance in favour of the phosphatases and switch off SAC signalling. [?]

    Are the incompletely de-phosphorylated HEC1 molecules the ones that retain MPS1 due to a lower affinity for microtubules?

    Is there a gradual reduction in Mps1 levels that tracks ever increasing microtubule occupancy, or is there a more switch-like behaviour?

     

    Does SAC strength correlate with Mps1 kinetochore levels?

    how is removal of Mps1 from microtubule-bound kinetochores compatible with its role in error correction?

    Can error correction be maintained by, for example, less Mps1 activity than needed for the SAC, or are relevant error-correction and SAC substrates affected differently by the same reductions in Mps1 activity?

    Elucidating the finer points of Mps1 regulation in the coming years will provide crucial insights into how genomic stability is ensured.

    Emphasis added.

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