Introduction on Cadherins

Cadherins, which is a cell surface molecules were originally identified in Chinese hamster V79 cells by Takeichi. These adhesion proteins are involved in Ca2+-dependent cell–cell adhesion as well as modulating crucial morphogenetic and differentiation processes during development. Cadherins are Ca2+ sensitive proteins and are readily degraded by proteolysis in the absence of Ca2+. It is one of the best studied classical family of cadherins which has a primary structure of 723 to 748 amino acids, similar in different cadherins [1]. When cells contact each other, Cadherins form trans- bonds at the site of contact between the opposing cells located at the site. Once the cells form trans-bonds, cadherins can regulate the formation of the cell–cell contact in three distinct ways: by reducing the local interfacial tension directly through adhesion tension and indirectly through signaling to the actomyosin cytoskeleton, and by establishing the mechanical coupling of contacting cells [2].

What is E-cadherin?

The human epithelial cadherin (E-cadherin) is a classical calcium- dependent cellular adhesion protein which is a type of cell surface transmembrane glycoprotein in epithelial tissue[3]. The protein structure consisting of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail [4], which interacts with several proteins collectively termed catenins [5]. E-cadherin plays an important role in the maintenance of the cellular adhesion and adherent junction in normal tissues. It is also been reported to participates in signaling pathways and can suppress tumor metastasis. Studies have shown that loss of E-cadherin function or expression has been implicated in epithelial-mesenchymal transition (EMT), which characterizes the transition from benign lesions to invasive and metastatic cancer [6].

Role of E-cadherin

E-cadherin has a significant role in formation and maintenance of cell- cell adhesion in epithelial tissues. Expression of E-cadherin starts very early, at two-cell stage in embryonic development. E-cadherin plays an important role in providing an early embryo to compact and helps the adhesion of the blastomeres. The function of E-cadherins lies primarily in the formation of adherens junctions [6].
The most important exhibit of E-cadherin’s function in development is its role in controlled epithelial- mesenchymal conversion [6]. E-cadherin modulate various signaling pathways which is important in maintaining the epithelial phenotype and regulating homeostasis of tissues [1].

Role of E-cadherin in cancer

E-cadherin is one of a potent tumor suppressor because down-regulation of E-cadherin is often found in malignant epithelial cancers [1]. It has been found that the E-cadherin gene is highly conserved and can play a major role in malignant cell transformation, and especially in tumor development and progression. E-cadherin adhesion stabilize the normal epithelial tissues and prevent apoptosis, but the tumor cells are resistance to apoptosis. Even tumor cells when detach from their adhesions are resistant to apoptosis. It is because of down-regulation of E-cadherins. However, tumor cells may regain their sensitivity to apoptosis when treated with E-cadherin activating mAbs. Apoptosis is induced in tumor by activating mAbs is due to their effects on adhesion or on one of the signaling pathways regulated by E-cadherin, including the hippo signaling pathway, the Wnt pathway, the small GTPases, Rac and Rho, or PI3Kinase signaling [9].
Disturbance of E-cadherin expression in different cancer
The reduced expression of E-cadherin has been reported in various cancers such as esophageal cancer, head and neck squamous, non-small cell lung cancer, invasive breast carcinoma as well as cervical cancer. Studies of E-cadherins in those caners explored the prognostic value of the down-regulation of E-cadherin protein, i.e., survival time and survival probability in confirmed cancer patients. Researches have been focusing on elucidating the role of E-cadherins in cancer diagnoisis. However, identification of E-cadherin as a biomarker in the early diagnosis and screening of precancerous lesions has yet to be thoroughly evaluated [6]. E-cadherin is expressed in normal adults in luminal epithelial cells of breast [5]. Moreover, in breast cancer cells, there is partial or total loss of E-cadherin expression which correlates with loss of differentiation characteristics, acquisition of invasiveness, increased tumor grade, metastatic behavior and poor prognoses [5].

Role of E-cadherin in signaling

Various catenins (α, β, and p120) are associated with cytoplasmic tail of E-cadherins to the cytoskeleton and mediate down-stream signaling effects. Some of the identified signaling pathways that linked to E-cadherins include the Hippo, Wnt, TGFβ, NF-κB, and other growth factor signaling pathways [7]. E-cadherin mediated cell signaling pathways is a considered as dynamic process which is regulated by several other signal transduction pathways. It is worth noted that E-cadherins are not only targets for signaling pathways that regulate adhesion, but may themselves transduce signals that regulate basic cellular processes, such as migration, proliferation, apoptosis and cell differentiation [6]. β-catenin encoded by CTNNB1 gene which is considered as a proto-oncogene. Mutations in CTNNB1 gene resulted in cancer due to damage in N-terminal region of β-catenin, β:TrCP binding motif. Damage to this binding motif disables ubiquitination and degradation of β-catenin [8].

Role of E-cadherin in Wnt signaling

E-cadherin/β-catenin complex mediateted signaling plays a central role in the Wnt signaling pathway. β-catenin is inactive in the cytoplasm by binding to the APC/GSK3β/Axin/CK1 degradation complex unless Wnt signal is activated. For Wnt pathway, β-catenin is considered the prime signal transducer. Wnt signaling phosphorylates the GSK3β which inhibits the E-cadherin/β-catenin complex and prevent the degradation process [3]. Activation of Wnt pathway causes translocation of intact β-catenin to the nucleus, where, together with the lymphoid enhancer factor (LEF)/T-cell factor (TCF), it activates a variety of transcription factors, resulting in positive or negative regulation by TCF/β-catenin. Therefore, tyrosine phosphorylation of β-catenin leads to beta-catenin signaling activation (and transcriptional impact), whereas β-catenin degradation inhibition in the presence of Wnt signaling is an inactivating mechanism [8].

Conclusion:

E-cadherin is an important cellular adhesion protein which can regulate cellular response generated by external signals the cell receives. It can regulate migration, proliferation, apoptosis and cell differentiation. E-cadherin is also regarded as a tumor suppressor gene. Reduced expression of E-cadherins can cause dysfunction of the cell- cell adhesion system, triggering cancer invasion and metastasis. Therefore, E-cadherin has elucidated insights into both embryogenesis and oncogenesis.

References

[1] C. Y. Loh et al., The e-cadherin and n-cadherin switch in epithelial-to-mesenchymal transition: Signaling, therapeutic implications, and challenges, vol. 8, no. 10. 2019.
[2] J. L. Maître and C. P. Heisenberg, “Three functions of cadherins in cell adhesion,” Curr. Biol., vol. 23, no. 14, pp. 626–633, 2013.
[3] H. Zhao et al., “Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications,” Front. Mol. Biosci., vol. 8, no. July, pp. 1–11, 2021.
[4] X. Ma et al., “Meta-analysis of downregulated E-cadherin as a diagnostic biomarker for cervical cancer,” Arch. Gynecol. Obstet., no. 99, 2022.
[5] G. Berx and F. Van Roy, “The E-cadherin/catenin complex: An important gatekeeper in breast cancer tumorigenesis and malignant progression,” Breast Cancer Res., vol. 3, no. 5, pp. 289–293, 2001.
[6] N. Pećina-Šlaus, “Tumor suppressor gene E-cadherin and its role in normal and malignant cells,” Cancer Cell Int., vol. 3, pp. 1–7, 2003.
[7] A. M. Mendonsa, T. Y. Na, and B. M. Gumbiner, “E-cadherin in contact inhibition and cancer,” Oncogene, vol. 37, no. 35, pp. 4769–4780, 2018.
[8] I. Kaszak, O. Witkowska-piłaszewicz, Z. Niewiadomska, F. N. Toka, and P. Jurka, “Role of Cadherins in Cancer — A Review,” pp. 1–17.

The post E-cadherin signaling; role in cancer and signal pathways appeared first on Online Biology Notes.

• One of the weirdest fate of the cell is the programmed cell death. Despite being odd fate it is essential for the body.
• Cell death has its own significance as such that it prevents our hands from being webbed, our embryonic tails from being prominent, our immune system from responding to our own proteins, and our brain from being jumbled with useless electrical connections.
• As a fact, the majority of cells produced in course of brain development also die during development.
• Cell death is regulated by cellular interactions in two fundamentally distinct ways.
• First, majority of the cells, if not all, in multicellular organisms need signals to remain alive.
  –  In case if such survival signals, frequently referred to as trophic factors, are lacking,  cells activate a “suicide” program.
• Secondly, in some developmental conditions, including the immune system, specific signals produce a “murder” program that kills cells.
• Recent studies suggest that whether cells commit suicide for absence of survival signals or are murdered by killing signals from other cells, death is mediated by a common molecular pathway.

Programmed Cell Death Occurs Through Apoptosis:

• The occurrence of cell death in programmed way is marked by a well-defined sequence of morphological changes, collectively termed as apoptosis.
• Apoptosis is a Greek word that refers “dropping off” or “falling off,” as in leaves from a tree.
• Dying cells at first shrink and condense and then fragment, releasing small membrane-bound apoptotic bodies.
• These apoptotic bodies are generally engulfed by other cells, such as macrophages. The nuclei condense and the DNA is fragmented.
•  Also, a lipid molecule termed as phosphatidylserine is displayed by the fragments of dying cells. This permits the other phagocytic cells to bind and eat the fragments.
• Significantly, the intracellular constituents are not released into the extracellular milieu to prevent the deleterious effects on neighbouring cells. Thus, it is also termed as the tidy way of cell death.
• The highly stereotyped changes accompanying apoptosis suggested to early workers that this type of cell death was under the control of a strict program.
• This program is crucial during both embryonic and adult life for the maintenance of normal cell number and composition.

Role of genes in apoptosis:

The genes involved in controlling cell death encode proteins with three different functions:

• “Killer” proteins are required for a cell to begin the apoptotic process.
• “Destruction” proteins are responsible for things like digesting DNA in a dying cell.
• “Engulfment” proteins are needed for phagocytosis of the dying cell by another cell.

• At first glance, engulfment seems to be simply an after-death clean-up process, but some evidence suggests that it is part of the final death decision.
• For example, mutations in killer genes always prevent cells from initiating apoptosis, whereas mutations that block engulfment sometimes allow cells to survive that would normally die.
• That is, cells with engulfment- gene mutations can initiate apoptosis but then sometimes recover.
• In contrast to apoptosis, cells that die in response to tissue damage manifest different morphological changes, termed as necrosis.
• Necrosis is typically a messy way of cell death i.e. during cell death, cells leak out the contents to extracellular environment.
• When the toxic chemicals come in contact to cell or if any injury occurs, the cell’s plasma membrane will now be fragile. It will be unable to regulate the flow of ions and water thus resulting in swelling up of cells.
• Typically, cells that undergo this process swell and burst, releasing their intracellular contents that can damage surrounding cells and frequently cause inflammation.
• Apoptosis is useful for the elimination of various cancerous or infected cells.
• It will detect the threats arising from the viral infections, DNA damage, precancerous cells and will eliminate them.
• The development and regulation of immune system is also performed by apoptosis.
• B and T cells are first tested if they respond to any of body’s own cell components. If they do so, they are eliminated right away by the apoptosis.
• For the maintenance of immune system, apoptosis has a significant role.
• When a pathogen enters the body, various immune cells specific to the pathogen divide largely and fight the pathogen.
• After combatting the pathogen, those immune cells are now not required and thus under apoptosis so as to maintain balance in immune system.

Apoptosis (Programmed cell death)

The post Apoptosis (Programmed cell death) appeared first on Online Biology Notes.

1. G1 (gap1) phase:

• The first stage of interphase is called the G1 phase (first gap) because, from a microscopic aspect, little change is visible. However, during the G1 stage, the cell is quite active at the biochemical level.
• It is characterized by a change in chromosome from condensed state to more extended state and series of metabolic events that leads to initiation of DNA replication. During G1 phase, chromatin fibres become slender, less coiled and fully extended and more active for transcription. The transcription results in synthesis of RNAs (tRNA, mRNA and rRNA) ad series of proteins molecules required for initiation of DNA replication.
• The length of G1 phase varies from cell to cell and also the length of G1 phase is more than other three phase in cell cycle.
• G1 phase represents 25-40% of generation time of a cell.
• G1 phase is very significant phase of cell cycle as the cell grows and accumulates the building blocks of chromosomal DNA and the associated proteins as well as sufficient energy reserves to complete the task of replicating each chromosome.
• Within G1 phase there is a definite check point at which DNA synthesis is initiated and once the biochemical events associated with that point have occurred cell proceeds towards division.

2. S (synthesis) phase:

• The synthesis phase of interphase is biochemically a phase of active DNA synthesis and histone synthesis.
• In the S phase, chromosome numbers doubles which is accomplished by DNA replication and associated proteins. Although some of the histone protein synthesis occurs in G1 phase, most of it is synthesized during S phase.
• DNA replication is semi conservative and discontinuous type which results in the formation of identical pairs of DNA molecules.
• After doubling of chromosome, sister chromatids are still firmly attached to the centromeric region.
• At the center of each animal cell, the centrosomes of animal cells are associated with a pair of rod-like objects, the centrioles, which are at right angles to each other. Centrioles help organize cell division. Centrioles are absent in plants and most fungi.
• The centrosome (centriole) is also duplicated during the S phase. The two centrosomes will give rise to the mitotic spindle, the apparatus that mediate the movement of chromosomes during mitosis.

3. Gap2 (gap2) phase:

• G2 phase follows S phase. This phase represents 10-25% of generation time of cell.
• In G2 phase chromosome consists of two chromatids ie the cell has twice the amount of DNA content.
• In the G2 phase, the cell restore its energy stores and synthesizes proteins necessary for chromosome manipulation.
• Some cell organelles are duplicated, and the cytoskeleton is dismantled to provide resources for the mitotic phase.
• There may be additional cell growth during G2. The final preparations for the mitotic phase must be completed before the cell is able to enter the first stage of mitosis

4. M (mitotic) phase:

• M phase follows G2 phase. During this phase cell divides into two daughter cell with equal distribution of chromosome among daughter cells. After M phase cell enter into G1 phase and next cell cycle is repeated. However, some cell after completion of mitosis do not enter into G1 phase, those cell are referred as G0 cells.
• M phase consists of following sub –phases;
  • During prophase, the nuclear membrane disappears, spindle fibers form, and DNA condenses into chromosomes (sister chromatids ).
  • During metaphase, the sister chromatids align along the equator of the cell by attaching their centromeres to the spindle fibers.
  • During anaphase, sister chromatids are separated at the centromere and are pulled towards opposite poles of the cell by the mitotic spindle.
  • During telophase, chromosomes arrive at opposite poles and unwind into thin strands of DNA, the spindle fibers disappear, and the nuclear membrane reappears.
• Cytokinesis is the actual splitting of the cell membrane; animal cells pinch apart, while plant cells form a cell plate that becomes the new cell wall.
• Cells enter the G₀ (inactive) phase after they exit the cell cycle when they are not actively preparing to divide; some cells remain in G₀ phase permanently.

Phases of Cell cycle

The post Phases of Cell cycle appeared first on Online Biology Notes.

• Eukaryotic chromosomes are located within a separate cellular compartment termed as nucleus.
• The length of DNA must be compacted by a remarkable amount in order to fit it inside nucleus.
• The compacting of DNA is accomplished by the binding of the DNA to many different cellular proteins.
• The formation of a highly organized DNA-protein complex, termed as chromatin, which is a nucleoprotein complex completes the packing.
• Chromatin is a dynamic structure capable of changing its shape and composition during the life of a cell (cell cycle).
• Chromatin can be defined as highly condensed chromosomes at metaphase stage, and very diffuse structures in course of interphase.
  

Chromatin composition and packaging

Histones:

• Histones are most abundant proteins in chromatin.
• Histones are small and positively charged proteins and are of 5 major types: H1, H2A, H2B, H3 and H4.
• Histones are characterized by the presence of high percentage of basic amino acids arginine and lysine.
• These amino acids are positively charged that give the histones a net positive charge facilitating the binding of histones to the negatively charged DNA.
• Histone and DNA are present in equal amounts in chromatin.
• A heterogenous variety of non-histone chromosomal proteins also are found in eukaryotic chromosomes.
• There are times where variant histones, with different amino acid sequences, are integrated into chromatin in place of one of the major histone proteins.
• The amino acid sequences of histones H2A, H2B, H3 AND H4 are highly conserved, even between distantly related species.
• Evolutionary conservation of these amino acid sequences highly indicates that histones perform the same basic role in organizing the DNA in the chromosomes of all eukaryotes.
• Structural studies suggest that the histones classes do share a similar tertiary structure, showing that all histones are ultimately evolutionarily related.

Role of H1:

• The next level of condensation of chromatin is brought about by histone H1.
• H1, in contrast to the other histones is not the part of the core particle.
• H1 binds to 20-22 bp of DNA, where the DNA joins and leaves the octamer.
• H1 binds both to the linker DNA at one end of the nucleosome and to the middle of the DNA segment wrapped around core histones.
• H1 serves to restrict the DNA into place and functions as a clamp around the nucleosome octamer.
• The core particle and it’s associated H1 histone are altogether called as the chromatosome.

Nucleosomes:

• When the chromatin is isolated from the nucleus of a cell and observed under an electron microscope, it resembles beads on a string.
• The repeating core of protein and DNA produced by digestion with nuclease enzymes is the nucleosome.
• Nucleosome is the basic structural and fundamental unit of chromatin and is the simplest level of chromatin.
• Nucleosome is a core particle formed when the DNA is wrapped about 2 times around an octamer of eight histone proteins (2 copies each of H2A, H2B, H3, H4).
• The DNA in direct contact with the histone octamer is between 145 and 147 bp in length.
• This configuration compacts the DNA by six times.

Linker DNA:

• Each chromatosome encloses about 167 bp of DNA (147bp around nucleosome+20bp bound by H1).
• Chromatosomes are present at regular intervals along the DNA molecule and are apart from each other by linker DNA.
• The size of linker DNA varies among cell types, in most cells, linker DNA comprises of about 30-40 bp.

The 30nm chromatin fiber:

• The nucleosomes compact themselves into a structure about 30nm in diameter, now termed as the 30nm chromatin fiber.
• There are two possible models for the 30nm fiber.
• They are:
  • Solenoid model: In this model, a linear array of nucleosomes are coiled into a higher order left handed helix, entitled as solenoid, with around six nucleosomes per turn.
  • Helix model: In this model, nucleosomes are arranged in a zigzag ribbon that twists or supercoils.

Higher order structure of chromatin:

• The next higher level of chromatin structure is represented by a series of loops of 30nm fibers, each anchored at its base by proteins in the nuclear scaffold.
• On average, each loop encloses some 20-100kb of DNA and measures about 300nm in length.
• The 300nm loops are packed and folded to result a 250nm wide fiber.
• Tight helical coiling of the 250 nm, in turn, yields the structure that is visible in metaphase- individual chromatids approximately 700nm in width.

Overall, this packaging produces a chromosome that is about 10,000 times shorter and about 400 times thicker, than naked DNA.

Chromatin structure, composition and packaging

The post Chromatin structure, composition and packaging appeared first on Online Biology Notes.

• As we know cells usually divide when they have doubled their content by volume, but actually the control of the process of cell division is very complex and occur precisely. All the process or steps of cell division occurs in sequence and also the cell know when to proceed and when to wait and stop cell division.
• A continuous cell division before DNA replication is completed or when chromosome or spindle fibers are damaged brings catastrophic consequences to cell or even organism. Therefore, every aspects of a cell is checked by its internal mechanism before proceeding to cell division.
• A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cell cycle can be halted until conditions are favorable.
• Numerous stops occur during the cycle to assess whether the next step should proceed or not and these stops are known as check point.
• A complex protein called Maturation promoting factor (MPF) have a significant role is cell maturation and mitotic division. It is also referred as mitosis promoting factor.
• MPF is composed of cyclin and cyclin dependent kinases, these two protein molecules are activated when combined together and are responsible for cell cycle to cross various checkpoints.
• In the cell cycle, there are three check points that involves cyclin-dependent kinases (cdks). Each cdk has its own specific cyclin that initiates either G1 phase, S phase, or M phase of cell cycle. Other check points that do not involve cdks also occurs at transition phases of cell cycles.
• Checkpoints in cell cycle is very important because it helps to halt the process of cell division if there is genetic damage, giving the cell to repair the damage before cell division. If the damage cannot be repaired then cell undergoes apoptosis and again if the check point mechanism is failed then cell become cancerous.

Various checkpoints in cell cycle:

i. G1 check point:

• The G₁ checkpoint determines whether all conditions are favorable for cell division to proceed or not. Such as damage to DNA and other external factors of cells are evaluated at this checkpoint. If the conditions are inadequate, the cell will not be allowed to continue to the S phase.
• G₁ checkpoint is also known as the restriction point at which the cell irreversibly commits to the cell division process. Cell set up certain requirements to be fulfilled by the cell to pass the check points.
• External factor such as growth factors play a vital role in carrying the cell past the G₁ checkpoint. The cell will only pass the checkpoint if it has an appropriate size and has adequate energy reserves.
• At this point, the cell also checks for DNA damage.
• A cell that does not meet all the requirements will not progress to the S phase. Those cells halt the cycle and attempt to correct the problematic condition, or the cell may undergoes inactivation into G₀ phase and await for further signals when conditions improve.
• If a cell meets all the requirements for the G₁ checkpoint, the cell will enter S phase and begin DNA replication.
• This G1 checkpoint involves signaled by cyclins and cyclin dependent kinases (CDKs).

ii. G2 check point:

• The G2 checkpoint ensures all of the chromosomes have been accurately replicated and that the replicated chromosome is not damaged before cell enters mitosis.
• G₂ checkpoint prevents the cell from entering into the mitotic phase if certain conditions are not met.
• If the checkpoint mechanisms detect problems with the DNA, the cell cycle is halted and the cell attempts to either complete DNA replication or repair the damaged DNA.
• If the DNA has been correctly replicated, cyclin dependent kinases (CDKs) signal the beginning of mitotic cell division

iii. M check point:

• The M checkpoint occurs at the end of the metaphase of mitosis.
• M checkpoint determines whether all the sister chromatids are correctly attached to the spindle fiber before the cell enters the irreversible anaphase stage.
• M checkpoint is also known as the spindle checkpoint because it determines whether all the sister chromatids are correctly attached to the spindle microtubules or not.
• At the end stage of metaphase, spindle fiber arising from opposite pole of cell attached to kinetochore of centromere of sister chromatid in equatorial plane. Then the cell enter into anaphase which is characterized by separation of sister chromosome toward opposite pole. Since anaphase is irreversible step in cell cycle, M phase check point is very crucial which ensure proper attachment of spindle to sister chromatids.
• M check point also involves signal from cyclin dependent kinases.

Regulation of cell cycle:

• The cell cycle is controlled by regulator molecules that either promote the process or stop it from progressing.

1.Positive regulation of cell cycle:

• Two groups of proteins; cyclins and cyclin-dependent kinases (Cdks), are responsible for promoting the cell cycle

i. Maturation promoting factor (MPF):

• MPF is composed of two protein complex; cyclin and cyclin dependent kinase (cdc2p).

• These two groups of proteins, called cyclins and cyclin-dependent kinases (Cdks), are responsible for the progress of the cell through the various checkpoints.

a. Cyclin:

• Cyclins are cell-signaling molecules that regulate the cell cycle
• There are four types of cyclins proteins- A, B, D and E
• The levels of the four cyclin proteins (A,B,D,E) fluctuate throughout the cell cycle in a predictable pattern
• Cyclin B is very important in mitosis.
• After the cell moves to the next stage of the cell cycle, the cyclins that were active in the previous stage are degraded.
• Cyclins regulate the cell cycle only when they are tightly bound to Cdks.
• To be fully active, the Cdk/cyclin complex must also be phosphorylated in specific locations.

b. Cyclin dependent kinases(CDKs):

• Cdks are kinase enzymes that phosphorylate other proteins or enzymes. Phosphorylation activates the protein by changing its shape.
• The proteins phosphorylated by Cdks are involved in advancing the cell to the next phase.
• The levels of Cdk proteins are relatively stable throughout the cell cycle; however, the concentrations of cyclin fluctuate and determine when Cdk/cyclin complexes form or not.
• The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints.

2. Negative regulation of cell cycle:

• Negative regulators halt the cell cycle.
• Negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21.
• If negative regulator proteins are damaged or become non-functional then it results in uncontrolled cell division leading to tumor or cancer.

i. Retinoblastoma proteins:

• Rb are a group of tumor-suppressor proteins common in many cells.

ii. P53

• P53 is a multi-functional protein. It is activated during G1 phase when there is DNA damage in the cell and cell employed the mechanism to repair the damage.
• When damaged DNA is detected, p53 protein halts the cell cycle and recruits enzymes to repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis to prevent the duplication of damaged chromosomes.
• As p53 levels rise, the production of p21 is triggered.

iii. p21:

• p21 enforces the halt in the cell cycle dictated by p53 by binding to and inhibiting the activity of the Cdk/cyclin complexes.
• In case of DNA damage condition or inadequate cell size, more and more p53 and p21 are produced which halt the cell cycle and prevent the cell to enter S phase.
• These negative regulators are known as tumor suppressor protein and gene that codes for such proteins are called tumor suppressor gene.
• Tumor suppressor either halt the cell until repair or leads to apoptosis thus preventing damaged cell from division. If mutation occurs in tumor suppressor gene, then those negative regulator proteins lost the function to halt the cell cycle leading cancerous cell of continuous growth and division.

Importance of cell cycle checkpoints and regulation

• The cell cycle of each cell must be precisely controlled and timed  to faithfully  and reproducibly  complete  the  developmental  program  in  every  individual.  Each type  of  cell in every  tissue must  control  its  replication  precisely  for  normal  development of complex  organs  such  as  the  brain  or the  kidney.  In a normal adult, cells divide only when and where they are needed.  However, loss of normal controls on cell replication is the fundamental defect in cancer.
• Cell cycle occurs with high accuracy and fidelity to assure that each daughter cell inherits the equal number of chromosome as of parent cell.
• Chromosome replication and cell division must occur in the proper order in every cell division.  If a cell undergoes the events of mitosis before the replication of all chromosomes has been completed, at Ieast one daughter cell will lose genetic information.
• Similarly, if a second round of replication occurs in one region of a chromosome before cell division occurs, the genes encoded in that region are increased in number out of proportion to other. Therefore, single round of DNA replication occurs in a cell.

Checkpoints and regulation of cell cycle

The post Checkpoints and regulation of cell cycle appeared first on Online Biology Notes.