The Cell Cycle (Клеточный цикл)

cell cycle, клеточный цикл


The cell cycle – cycle of duplication and division; varies in different organisms and in one at different periods of time.

Overview

  • Growth and duplication of chromosomes
  • Segregation of chromosomes
  • Division

M-phase:

  1. Mitosis (nucleus division)
  2. Cytokinesis (cell division)

Main goal: to duplicate DNA and segregate the
copies into 2 daughter cells.

The control system

  • system of regulatory proteins governs correct cell-cycle progression at definite critical states
  • if mishap occurs the control system can
    arrest the cell cycle

Checkpoints of the cell cycle

  • late G1 – Is environment favorable?
  • G2→M – Is DNA replicated correctly?
  • M: meta→ana – Are all chromosomes
    attached to the spindle?

CDKs – main proteins of the control system

  • CDKs are present in the cell during the whole
    cell cycle and are periodically switched on/off
  • CDKs cotain inhibitory phosphate and normally are inactiveare inactive
  • Regulated by cyclins
  • [Cyclin/CDK] control different phases and phosphorylate different proteins

Regulation of [Cyclin/CDK] activity

  • phosphorylation/ dephosphorylation of the CDKs
  • binding of CDK inhibitor proteins
  • proteolysis of cyclins
  • transcriptional regulation

G1-phase

  • estimation of internal and external conditions
  • S-, M-CDKs are inactive to let the cell grow

Mitogens stimulate progression to S-phase

Mitogens – extracellular signals from other cells switching on signaling pathways that promote progression to S-phase

Negative control – Retinoblastoma protein (Rb): Rb is abundant in nucleus and is bound to transcription regulators, therefore, arrests cell division.

  1. Mitogens bind to receptors, switching on signaling pathways that activate CDKs.
  2. CDKs phosphorylate Rb twice inactivating it.
  3. Freed transcription regulators activate the transcription of genes required for cell division.

DNA damage halts progression to S-phase

  1. DNA damage causes activation of kinases that phosphorylate p53.
  2. Activated p53 stimulates the transcription of the gene that encodes the CDK inhibitor p21
  3. p21 inhibits CDK complexes and G1-S transition is arrested

The cell has time to repair damaged DNA. If the DNA damage is too severe to be repaired, p53 can induce the apoptosis.

S-phase

  1. Initiation of DNA replication ORC (origin recognition complex) binds to the replication origin.
  2. Cdc6 binds to ORC and these proteins associate with Mcm helicase bound to Cdt1. ORC with Cdc6 load inactive helicase around the DNA, forming the prereplicative complex (preRC).
  3. S-CDKs phosphorylates ORC and initiator proteins. Another kinase, DDK, phosphorylates the helicase subunit. As theresult, the helicases are activated and unwind the DNA, DNA polymerase is recruited to the origin, the replication begins.

Prevention of new preRCs formation until the end of mitosis

S-CDK phosphorylates ORC and Cdc6.
APC/C is inactivated in late G1 ⇒ accumulation of Cdt1 inhibitor, geminin, Cdt1 destruction.

G2-phase

  1. Synthesis of M-cyclin increases in G2 and M leading to the assembly of M-CDK complex.
  2. M-CDK is phosphorylated by CAK (CDK activating kinase) at an activating site and by Wee1 (CDK inhibitor) at inhibitory sites.
  3. Activated Cdc25 removes inhibitory phosphate from M-CDK activating it.

Positive feedback loop: once activated, M-CDK can activate its activator (Cdc25)
and inhibit its inhibitor (Wee1).

Mitosis

Prophase

  1. Condensing duplicated chromosomes consist of two sister chromatids.
  2. Formation of mitotic spindle between two centrosomes is promoted by M-CDK.

Proteins help to segregate chromosomes

  • After duplication (before condensation) sister chromatids are tightly held together along the length by cohesins.
  • Condensins help to segregate chromatids into more compact structures.

Prometaphase

  1. The process of nuclear envelope disassociation is triggered by phosphorylation of nuclear lamina
    proteins and porins.
  2. Kinetochores recognize special sequences on centrosome and assembly on it. Chromosome has two kinetochores facing opposite directions.
  3. Bi-orientation: chromosome is bound to both poles of mitotic spindle. Attachment to the opposite poles causes tension in kinetochores that signals about correct fixation.
  4. Chromosomes take part in bi-orientation – mitosis is possible in the absence of centrosomes.

Metaphase

Formation of metaphase plate: chromosomes being attached to the spindle align at its equator and oscillate thus generating tension.

Forces that move chromosomes in prometa – and metaphases

  1. Force produced by kinetochore proteins.
  2. Microtubule flux – depolymerization  of "-" end and growth of "+" end keep the length constant and cause poleward movement.
  3. Polar wind generated by motor proteins that move chromosome arms to "+" end.

Anaphase

Anaphase A – chromosome segregation

  1. Sister-chromatid separation follows cohesin destruction.
  2. Cohesin is destroyed by separase that is inhibited by securin before anaphase. At the beginning of anaphase securin is destroyed with the help of APC.

Anaphase B – poles move apart

  1. Spindle poles movement is provided by motor proteins: sliding force between interpolar microtubules and pulling force that pulls poles to the cell cortex.
  2. Spindle assembly checkpoint: unattached chromosomes send stop signals blocking APC activation. Thus,
    sister chromatids are held together until all chromosomes are attached.

Telophase

  1. Daughter chromosomes are separated.
  2. The mitotic spindle is disassembling.
  3. Chromosomes decondense.
  4. The nuclear envelope is reorganized (lamina proteins and porins are dephosphorylated, vacuoles gather around chromosomes and fuse).

Cytokinesis

Process of cytoplasm division in two that starts in anaphase

  1. Overlapping central spindle microtubules activate proteins that signal to assembly the contractile ring midway the poles.
  2. Contractile ring consists of actin and myosin filaments attached to the proteins of plasma membrane.
  3. Asymmetric division results in different cell types.

Cytokinesis in Plant cells

Alberts, Bruce, author. Molecular biology of the cell / Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter; with problems by John Wilson, Tim Hunt. — Sixth edition.


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