Cell Cycle Checkpoints

9 Key excerpts on "Cell Cycle Checkpoints"

• 

  eBook - ePub

  Rediscovering Cancer: From Mechanism to Therapy

  • Sayali Mukherjee, Somali Sanyal, Sonia Chadha, Sayali Mukherjee, Somali Sanyal, Sonia Chadha(Authors)
  • 2018(Publication Date)
  • Apple Academic Press

    (Publisher)

  Cell cycle is thus a highly complex process, which requires a tight coordination of various mechanisms that control different stages of DNA synthesis, replication, and segregation into daughter cells. This chapter has detailed the concerted and sequential activities of cyclins, CDKs, and various interdependent signal transduction pathways in maintaining the integrity and progression of cell cycle in normal cells. Concurrently, it highlights the susceptibility of cells to DNA damage by alteration in any component of cell division machinery.

  3.6 Summary

  • Normal cell cycle progression is maintained and continuously monitored by an intricate network of signal transduction pathways comprising cyclins, CDKs, CKIs, and several checkpoint gene products.
  • Deregulation associated with synthesis, amplification, or mutation of cell cycle regulator proteins, tumor suppressors, and transcription factors is reported in a wide variety of human cancers. Therefore, loss of cell cycle checkpoint control is one of the principle causes of genetic instability that lead to malignancies.
  • Thus, elucidating novel molecular mechanisms in cell cycle progression and checkpoint control can not only help in early detection of cancers and serve as prognostic markers but may also aid in predicting cancer susceptibility.
  • Better characterization of known defects of pivotal checkpoint genes may help to reconstruct altered DNA damage responses aiding in designing targeted cancer therapeutic strategies. One such example is the cyclin-dependent kinase inhibitors. These low-molecular-weight units constitute attractive pharmacological targets for silencing or disrupting kinase hyperactivity in human cancers.
  • Finally, because most of the components of human cell progression and control pathways play an equally essential role in other physiological processes like transcription, differentiation, neuronal, immunological response, and senescence, effective therapeutic strategies involving these pathways would promote better health outcomes.

  KEYWORDS

  • Cancer
  • cell cycle
  • Cell Cycle Checkpoints
  • cyclin
  • DNA damage

  References

  1. Dubrovsky, J. G. & Ivanov, V. B. (2003). Celebrating 50 years of the cell cycle.

  Nature

  ,

  426

  Sign up to read

  Learn more about book
• 

  eBook - ePub

  Genome Duplication

  • Melvin DePamphilis, Stephen Bell, Stephen D. Bell(Authors)
  • 2010(Publication Date)
  • Garland Science

    (Publisher)

  Chapter 13 CHECKPOINTS

  In the previous chapter, we learned that cell-division cycles are controlled by a series of feedback loops that ensure a linear progression of events from cell growth to genome duplication to cell division. In addition, eukaryotic cells employ at least four mechanisms (Figure 12-12 ) to prevent DNA from undergoing more than one round of replication in a single cell cycle, and at least four mechanisms (Table 12-6 ) that permit some eukaryotic cells to bypass these controls and duplicate their nuclear genomes more than once without undergoing cytokinesis (termed developmentally regulated polyploidy). Here we describe the cell’s police force, mechanisms that check the cell’s progress at various points along the road to cell division. These cell-cycle checkpoints, as Leland Hartwell called them in 1989, are surveillance mechanisms that arrest the cell cycle at specific stages in response to problems either in chromosome replication or in cell division. They ensure that cells do not begin genome duplication before they have produced the components required for its completion, that DNA damage will not derail the replication process, that cells will complete genome duplication before attempting to divide, and that each cell receives a complete set of chromosomes during cytokinesis. Checkpoints presumably exist in all living organisms, although only those in bacteria and eukarya (primarily yeast and mammals) have been characterized extensively.

  Cell-cycle checkpoints sense an imbalance in the normal flow of events and then respond by blocking the transition to the next event (Figure 13-1 ). Based on the event they sense and on the transition they block, cell-cycle checkpoints fall into three groups: those that restrict cell growth, those that sense changes in DNA structure, and those that sense changes in mitotic structures. Although checkpoints are not essential for cell division, they are essential for the existence of living organisms. When checkpoints are eliminated by mutation or bypassed by other means, the results are infidelity of chromosome transmission, increased susceptibility to agents that damage DNA, and cell death. Inactivation of checkpoint pathways leads directly to genome instability, and genome instability leads to cancer. Given the differences in their genetic complexity (Table 1-4 ), it comes as no surprise that the complexity of checkpoints increases from bacteria to yeast to simple metazoa to complex metazoa such as humans. Nevertheless, common principles are evident. Both bacteria and eukarya have a restriction checkpoint and at least one DNA damage checkpoint (Figure 13-2 ). Moreover, these two checkpoints sense the same defects and respond in analogous ways, even though the pathways and proteins involved differ markedly (Table 13-1

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Signal Transduction in Cancer

  • Mohamed A. Selmy(Author)
  • 2019(Publication Date)
  • Delve Publishing

    (Publisher)

  7.3.3. Control of DNA Integrity The cell cycle is controlled at the level of numerous checkpoints, which can stop its progression; these checkpoints are under the control of the proteins that survey the integrity of newly synthesized DNA and evaluate the absence of lesions that would lead to hereditary abnormalities (Figure. 39). These proteins are serine/threonine kinases whose harmful mutations Signal Transduction in Cancer 98 result in some diseases that are characteristic of DNA fragility such as ‘‘ataxia telangiectasia’: ATM, ATR and DNAPK. These kinases activate by phosphorylation the checkpoint kinases CHK1 and CHK2; ATM special substrate is CHK1 and ATR special substrate is CHK2. CHK1 and CHK2 can phosphorylate in order the CDC25 phosphatases (CDC25A for CHK1 and CDC25B/C for CHK2), but these phosphorylations constrain CDC25 activity, stopping, therefore, the activation of the cyclin–CDK complexes necessary for cell cycle progression through the G1 → S transition or through the G2→M transition. CHK2 activates, in addition, the inhibitory kinase WEE1, which sustains the inhibition of CDK1 and maintains the cells in G2 phase. Additionally, CHK2 hinders PLK1 and stops thus the realization of the early mitotic events, since PLK1 is implicated in centrosomes formation, chromosomes separation and mitotic spindle set up. Figure. 39 Cell Cycle Checkpoints and control of DNA integrity (Spoerri, Oo, Larsen & Haass, 2015). CHK2 is also capable of activation by phosphorylation the transcription factor p53, which is therefore at the crossroads between the information attained from DNA integrity and the implementation of the pathways targeting the prevention of the propagation of mutagenic DNA damage. p53 is normally present in the cell at very low concentrations, thanks to its binding to its E3 ubiquitin ligase, MDM2 (murine double – minute homologue), which drives it to the proteasome.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Genome Stability

  DNA Repair and Recombination

  • James Haber(Author)
  • 2013(Publication Date)
  • Garland Science

    (Publisher)

  DNA DAMAGE CHECKPOINTS AND GENOME INSTABILITY CHAPTER 16 One cannot discuss the basis of genome stability without including the role of DNA damage checkpoints. References to the actions of check-point kinases have crept into many chapters, but it is worth consolidating some ideas in one chapter. This is a subject worthy of an entire book, and only some of the most salient points will be reviewed here. Cells detect DNA damage in several ways and activate both a G1-to-S and a G2-to-M checkpoint. These checkpoints delay cell cycle progression, presumably to give the cell more time to repair damage before entering S phase or to initiate mitosis, respectively. In this brief review we will not examine the DNA replication checkpoint (often called the S-phase response) in which different sensors feed into the same network of kinases described here for the DSB checkpoint response to stabilize DNA if replication itself is compromised. Checkpoint-mediated arrest of the cell cycle provides an opportunity for DNA repair processes to be completed before mito-sis would segregate broken or covalently linked chromosomes. In many organisms, checkpoint-mediated apoptosis affords a way to destroy damaged cells before they undergo genome rearrangements that might promote cancer. The astonishing number of rearrangements in human cancer cells mostly appear in cells that have lost their ability to repair DSBs by homologous recombination, and, in addition, have lost their ability to restrain cell growth in the face of damage. 16.1 THE DNA DAMAGE CHECKPOINT PROVIDES A CELL CYCLE DELAY TO ALLOW DNA REPAIR The first identification of a DNA damage checkpoint was accomplished by Ted Weinert and Leland Hartwell who studied the viability of budding yeast cells lacking the RAD9 gene after exposure to ionizing radiation.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  DNA Repair and Cancer

  From Bench to Clinic

  • Srinivasan Madhusudan, David M. Wilson III(Authors)
  • 2013(Publication Date)
  • CRC Press

    (Publisher)

  Progression through each cell cycle phase and transition from one to the next are monitored by sensor mechanisms, called checkpoints. Some are active during the unperturbed normal cell cycle to maintain the correct order of events, but in the presence of DNA damage, are activated to allow cells time to properly repair the damage, thus safeguarding the integrity of the genome (Niida and Nakanishi 2006). Figure 4. Cyclin-CDKs complexes and their inhibitors involved in cell cycle progression control. The cell cycle of eukaryotic cells can be divided into four successive phases: M phase (mitosis), in which the nucleus and the cytoplasm divide; S phase (DNA synthesis), in which the DNA in the nucleus is replicated, and two gap phases, G1 and G2. The transition from one phase of the cell cycle to the next is controlled by cyclin–CDK (cyclin-dependent kinase) complexes, which ensure that all phases of the cell cycle are executed in the correct order. Progression through the mitotic cycle is driven by the actions of CDKs and their activating cyclin subunits. CDK activity is suppressed through interactions with two main families of inhibitory proteins (CDK inhibitors or CDKIs): the INK4 family that exhibits selectivity for CDK4 and CDK6, and the CIP/KIP family that has a broader range of CDK inhibitory activity (Adapted from (Dehay and Kennedy 2007)). 438 DNA Repair and Cancer: From Bench to Clinic The regulation of cell cycle progression in response to DNA damage shares with the DNA repair processes a common signal transduction response, involving the ATM/Chk2 and ATR/Chk1 signal transduction pathways. Activated, the signal transducers phosphorylate and promote the degradation or sequestration of effector Cdc25s, specialized phosphatases that activate the CDKs. The inactivation of the Cdc25s, as well as the accumulation of the effector protein p53 (see Chapter 12), which is induced by its phosphorylation, leads to the arrest of the cell cycle progression.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Development Biology

  • Edward Bittar(Author)
  • 1998(Publication Date)
  • Elsevier Science

    (Publisher)

  Again, genetics can be applied because if a mutation can re- move the dependence of certain cell cycle events, then a checkpoint exists. Check- points are used to ensure that DNA replication is completed, DNA repaired and chromosomes segregated. TIMER CONTROLS A number of other controls are coupled to those already described; it seems that mechanisms for monitoring time as well as cell mass and growth rate must operate in order to ensure orderly progress of cellular growth and division (Murray and Kirschner, 1989). Various models have been proposedmsome consisting of fixed series of reactions that take a definite time for completion, and others involving a self-sustained oscillatory mechanism of the type provided by a limit-cycle (Figure 3). The state of a limit-cycle oscillator depends on two variables, and has four mini- mal requirements: (i) that A is converted to B; (ii) negative feedback (that B inacti- vates or destabilizes A); (iii) that B is itself unstable and thus has a characteristic half-life; and (iv) that the attainment of a critical threshold of A provides the sys- tem's signal output. There have been many candidates for the role of mitotic oscillator. The currently favored one involves cyclin-cdc2 kinase interaction (Hyuver and Le Guyader, 1990; Goldbeter, 1991; Norel and Agur, 1991; Novak and Tyson, 1993; Tyson et al., 1996). Although it is sometimes referred to as the cell cycle clock, the mitotic oscillator is not a clock in the strict sense. This is because a clock has to be temperature- compensated whereas the cell division cycle is highly temperature-dependent (Lloyd, 1992; 1997). The best known cases of strict timekeeping of cell division are Cell Cycle Control E9 I 9 s t A ~ B.. [ l . . . . . . . [A]cRIT [ ] / / t, iB / V / 1',, / t [A] TIME-~ [ B]...-~ Figure 3. The cell division cycle as a limit-cycle oscillator. those of lower eukaryotes (e.g., planktonic algae) that divide each day at dawn.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  DNA Replication

  Current Advances

  • Herve Seligmann(Author)
  • 2011(Publication Date)
  • IntechOpen

    (Publisher)

  Part 5 Proteins in Replication 22 Faithful DNA Replication Requires Regulation of CDK Activity by Checkpoint Kinases Claus Storgaard Sørensen 1 , Halfdan Beck 1 , Viola Nähse-Kumpf 2 and Randi G. Syljuåsen 2 1 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2 Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, 1 Denmark 2 Norway 1. Introduction The most fundamental aspect of cell division is the precise transfer of genetic material to daughter cells. In order to maintain genome stability the daughter cells need to receive an exact copy of the genetic material from the original cell. This is achieved mainly through two processes. First, the genetic material is carefully copied during the process of DNA replication in S phase of the cell cycle, and thereafter it is precisely segregated into two identical daughter cells during mitosis (M phase). Additional control and preparation for DNA replication occurs in G1 phase, which is the gap phase between M and S phases, and DNA repair processes and preparation for mitosis occurs in G2 phase, which is the gap phase between S and M phases. A major obstacle for genome stability is endogenous sources of DNA damage during S phase, which can lead to mutations or chromosome rearrangements if left unrepaired. Such mutations and chromosome rearrangements can again cause cell death or lead to the development of diseases associated with genomic instability such as cancer and neurodegenerative disorders (Jackson and Bartek, 2009). The cellular mechanisms that protect against induction of endogenous DNA damage during S phase are therefore particularly important. DNA replication is tightly regulated by a number of signaling pathways including regulators of Cyclin-Dependent Kinase (CDK) activity.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Biomolecular Action of Ionizing Radiation

  • Shirley Lehnert(Author)
  • 2007(Publication Date)
  • CRC Press

    (Publisher)

  6. G 2 ! M : Mitotic or B-type cyclins associate with cdk1 to control entry and exit from mitosis. Dephosphorylation of the inhibitory sites by cdc25 phosphatase and activation of cyclin B triggers cdk1 activation essential for entry into mitosis. The abrupt and controlled degradation of cyclin B by the ubiquitin– proteasome pathway allows exit from mitosis. The retinoblastoma protein pRb is also dephosphorylated at this time. In summary, as the cell-cycle proceeds, a tightly regulated sequence of events unfolds around each cell-cycle transition. For each of these scenarios the script is essentially the same, but the identities and roles of the players change. Radiation-induced damage to DNA in normal nonmutant cells instigates an unscheduled break in the action during which damage control can occur. 8.4.2 Radiation-Induced Cell-Cycle Arrest Delays at cell-cycle checkpoints are believed to prevent the replication of damaged DNA (G 1 = S and intra-S checkpoints) or segregation of damaged chromosomes (the G 2 = M checkpoint). Indirect evidence for the importance of such controls in the maintenance of genome stability is provided by genetic disorders such as A-T, ATLD, and NBS, which are characterized by checkpoint deficiencies, are radiosensitive and associated with a high incidence of tumorigenesis. However, as described, there is evidence that the radiosensitivity associated with syndromes such as A-T may also cor-relate with a defect in DNA repair as well as with a cell-cycle checkpoint deficiency. A number of DNA repair proteins have been found to be regu-lated either transcriptionally or post-translationally after DNA damage in a Cellular Response to DNA Damage 193 manner that requires ‘‘checkpoint’’ genes [25] while several repair proteins have been established as substrates for checkpoint kinases.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Genome and Disease

  • J. -N. Volff, M. Schmid(Authors)
  • 2006(Publication Date)
  • S. Karger

    (Publisher)

  Volff J-N (ed): Genome and Disease. Genome Dyn. Basel, Karger, 2006, vol 1, pp 116–130 The Spindle Checkpoint and Chromosomal Stability W. Qi, H. Yu Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Tex., USA Abstract Normal human somatic cells contain 46 chromosomes (22 pairs of autosomes and two sex chromosomes). Chromosome missegregation leads to abnormal numbers of chromo-somes or aneuploidy. This form of genetic instability alters the dosages of large subsets of genes, which can result in severe disease phenotypes. Most human cancer cells are aneu-ploid. It is generally believed that aneuploidy contributes to cancer formation. The spindle checkpoint is a cell-cycle surveillance mechanism that ensures the fidelity of chromosome segregation during mitosis and meiosis. In this article, we review our current understanding of the molecular basis of the spindle checkpoint and the recent evidence that links the mal-function of this checkpoint to aneuploidy and tumorigenesis. Copyright © 2006 S. Karger AG, Basel Cancer has long been recognized as a disease associated with genetic instability. A prevalent form of genetic instability in human cancers is chromo-some instability (CIN) [1, 2]. As compared to normal cells, cancer cells with CIN gain or lose their chromosomes at a higher rate and contain abnormal num-bers of chromosomes (aneuploidy). The molecular basis of CIN is not yet fully understood. However, it has become increasingly clear that malfunction of a cell-cycle surveillance mechanism called the spindle checkpoint contributes to CIN and aneuploidy. The Spindle Checkpoint The chromosomes are duplicated once and only once during each cell divi-sion [3]. The duplicated chromosomes are physically tethered together by the The Spindle Checkpoint and Chromosomal Stability 117 cohesin protein complex and are packaged into sister chromatids during mitosis [3].

  Sign up to read

  Learn more about book