Cell Cycle

Definitions

• Chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure: the combination of nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance and proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis that makes up chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure
• Histones Histones Small chromosomal proteins (approx 12-20 kd) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. DNA Types and Structure:
  • Most common protein in chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure
  • Organize DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure, allowing it to be more tightly or loosely wound
• Chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure:
  • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and protein-containing subunits in which genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure are organized
  • Usually string-like and diffuse, during mitosis condense into discrete rod-like structures
• Sister chromatid: 1 of 2 identical halves of a replicated chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics
• Centrioles: cylindrical organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles that function as one of the attachment Attachment The binding of virus particles to virus receptors on the host cell surface, facilitating virus entry into the cell. Virology poles of the mitotic spindle in a replicating cell (the other end being a kinetochore)
• Centrosomes: organelle containing centrioles
• Kinetochore: protein structure that attaches to the central zone of a chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics (centromere) to which one of the ends of the mitotic spindle attaches in a replicating cell (the other end being the centrioles)
• Centromeres: the region of the chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics to which the microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton of the mitotic spindle attach via the kinetochore
• Mitotic spindle: the microtubule structure created from the disassembled cytoskeleton Cytoskeleton The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. The Cell: Cytosol and Cytoskeleton of a cell along which chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure are pulled when they are separated during mitosis

Overview

The cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation describes the cyclic sequence of events through which a eukaryotic Eukaryotic Eukaryotes can be single-celled or multicellular organisms and include plants, animals, fungi, and protozoa. Eukaryotic cells contain a well-organized nucleus contained by a membrane, along with other membrane-bound organelles. Cell Types: Eukaryotic versus Prokaryotic, proliferating parent cell splits into 2 identical daughter cells.

G0

• Mature, differentiated cells outside the cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation are in this reversible, resting state.
• Low concentration of growth factor and high population density keep cells in G0.
• Normal metabolism occurs, but there is no cell division.
• Specific triggers Triggers Hereditary Angioedema (C1 Esterase Inhibitor Deficiency), such as growth factors, induce some cells to return to G1.

Interphase

G1, S, and G2 phases are grouped together as interphase.

• G1 (gap 1): duration = approximately 12 hours
  • Occurs immediately after mitosis (cell is half its normal size)
  • Period of cell-volume growth 
  • RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure and protein synthesis Synthesis Polymerase Chain Reaction (PCR) take place.
  • Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis and cellular constituents required for mitosis (e.g., microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton) are created.
• S ( synthesis Synthesis Polymerase Chain Reaction (PCR)): duration = 8–12 hours
  • Chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure double, creating identical pairs of sister chromatids ( diploid Diploid The chromosomal constitution of cells, in which each type of chromosome is represented twice. Symbol: 2n or 2x. Basic Terms of Genetics → tetraploid set)
  • Quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement assurance phase:
    • Ensures the accuracy of replication
    • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure mismatch repair Mismatch repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome occurs
  • Machinery for mitosis is prepared:
    • Centrosomes duplicate
    • Centriole separate
    • Histones Histones Small chromosomal proteins (approx 12-20 kd) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. DNA Types and Structure synthesized
• G2 (gap 2): duration = 1.5–3 hours
  • Replication of certain organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles
  • Preparation of structures used to move chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure ( cytoskeleton Cytoskeleton The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. The Cell: Cytosol and Cytoskeleton is dismantled)
  • Specific proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis that are required for cell division (e.g., RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure molecules) are synthesized.
  • Replication is checked using repair mechanisms.
  • The cell completes the interphase and is ready for mitosis.

Cell Division (Mitosis)

During mitosis, the cell’s duplicated DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure is separated and distributed to 2 identical daughter cells. The process lasts approximately 1 hour.

• Prophase:
  • Chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure condense, becoming visible.
  • Microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton assemble, creating the mitotic spindle attached to the centrioles.
  • Centrosomes migrate toward opposite poles of the cell.
  • Nucleolus Nucleolus Within most types of eukaryotic cell nucleus, a distinct region, not delimited by a membrane, in which some species of rRNA are synthesized and assembled into ribonucleoprotein subunits of ribosomes. In the nucleolus rRNA is transcribed from a nucleolar organizer, i.e., a group of tandemly repeated chromosomal genes which encode rRNA and which are transcribed by RNA polymerase I. The Cell: Organelles is no longer visible. 
  • Nuclear envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology begins to dissolve.
• Prometaphase:
  • Kinetochores assemble at the chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics centromeres.
  • Free ends of microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton connect to the kinetochores.
  • Centrosomes reach the opposite poles.
• Metaphase:
  • Chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure are aligned along the equatorial region (metaphase plate) of the cell. 
  • Each sister chromatid is attached to a mitotic spindle originating from opposite poles.
  • The nuclear envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology completely dissolves.
• Anaphase: 
  • Kinetochores break down.
  • Sister chromatids become single chromatids or chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure.
  • Chromatids migrate to opposite poles along the mitotic spindle. 
  • Spindle fibers opposite the chromatids elongate, stretching the cell into an oval.
• Telophase:
  • New nuclear envelopes form around the decondensing chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure.
  • The spindle apparatus dissolves. 
  • “Cleavage furrow” splits the cell in 2 ( cytokinesis Cytokinesis The process by which the cytoplasm of a cell is divided. Meiosis)
  • Each of the daughter cells develops a complete cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane.
  • Both daughter cells are completely separated from each other.

Regulation of the Cell Cycle

The cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation is tightly regulated. Not passing a checkpoint should trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death ( apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage). Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage failure results in mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations accumulation, leading to disease.

The cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation begins when the cell has:

• A sufficient minimum size
• Appropriate nutritional conditions
• Been stimulated by growth factors, in addition to the absence of anti-mitogenic signals

Molecules regulating the cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation

• Positive regulators: Presence at appropriate concentrations permits the cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation to progress.
  • Cyclins:
    • Regulatory proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis released in response to internal and external stimuli at specific stages of the cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation.
    • 4 different cyclin concentrations fluctuate predictably during the cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation.
  • Cyclin-dependent kinases Kinases Macrolides and Ketolides (CDK) are protein kinases Kinases Macrolides and Ketolides that are:
    • Activated by cyclins and protein kinases Kinases Macrolides and Ketolides (via phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing)
    • Inhibited by protein phosphatases Phosphatases Oxazolidinones (via dephosphorylation) and cyclin-dependent kinase inhibitors Cyclin-Dependent Kinase Inhibitors Targeted and Other Nontraditional Antineoplastic Therapy (CKIs)
  • Nuclear localization sequence (NLS) allows cyclins to enter the cell nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles as a heterodimer with CDKs.
• Negative regulators: Activation of these factors blocks the cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation. 
  • p53 and p21: halt cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation if DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure damage is detected
  • Retinoblastoma Retinoblastoma Retinoblastoma is a rare tumor but the most common primary intraocular malignancy of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or non-heritable. Retinoblastoma protein: halts the G1/S transition
  • If hyperphosphorylation occurs due to cyclin-D/CDK 4/6 dimers → transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of cyclin E and other proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis for progression to S phase begins.

Restriction points

• Later G1 phase (G1S checkpoint): irreversible 
  • Regulated by CDK2 and cyclin E
  • Transition between the G1 and S phases determines cell progression to cell division or dormancy in G0 phase.
• End of the G2 phase (G2M checkpoint)
  • Regulated by CDK1 and cyclin B
  • Checkpoint for favorable environmental conditions and correct and complete replication of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure 
    • Incomplete genome Genome The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics at this stage will result in cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death.
    • M-phase promoting factors (MPF), which are cyclin-CDK heterodimers, play an important role in this checkpoint.
• During metaphase (spindle checkpoint): irreversible
  • Ensures that all chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure adhere to the spindle microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton prior to separation in anaphase
  • Tension on the spindle fibers → production of anaphase-promoting complex ( APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis) 
  • APCs promote breakdown of connexin (kinetochore) proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis between sister chromatids.
• G1 and G2 phases have further DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure damage checkpoints.
  • The cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation can be arrested until damage has been repaired.
  • If the DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure is irreparable, apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage is triggered.