Cell Cycle Checkpoints
The cell
cycle is a meticulously planned and well-orchestrated sequence of activities
that control the expansion, maturation, and upkeep of multicellular organisms.
It makes sure that cells replicate precisely and effectively, protecting
against mistakes that may cause illnesses like cancer. Cell cycle checkpoints
are important regulatory systems at the centre of this process.
Cell cycle
checkpoints are surveillance sites put at specific intervals to watch on the
integrity and progress of the cell cycle. Before allowing the cell to move on
to the next stage of the cell cycle, these checkpoints serve as quality control
stations, making sure that each phase has been correctly completed.
There are three main checkpoints in the cell
cycle process G1 checkpoint, G2 checkpoint and the mitotic checkpoint (spindle
checkpoint)
Functioning of major checkpoints
1) G1 Checkpoint (Restriction checkpoint)
· Environmental Assessment: The cell assesses its surroundings, including the availability of nutrients and extracellular signals from nearby cells, before moving into the S phase (the period of synthesis).
· DNA integrity verification: The cell verifies the accuracy of its DNA. It checks if there is any mutation or damage in the DNA due to radiation or chemicals.
· Checkpoint proteins: Cyclin-dependent kinases (CDKs) and cyclins are important checkpoint proteins that are engaged in the G1 checkpoint. The checkpoint is either passed or not crossed depending on the presence of particular cyclin-CDK complexes.
· Decision Point: The cell is given the go-ahead to enter the S phase if the environment is favourable and the DNA remains unharmed. This indicates that the cell is fully engaged in the cell cycle and will carry out DNA replication. The cell may delay entering the S phase, engage DNA repair mechanisms, or go into a quiescent state (G0 phase) if conditions are unfavourable or there is DNA damage.
2) G2 Checkpoint:
· Confirmation of DNA Replication: The cell gets ready for mitosis during the G2 phase. It determines if DNA replication during the S phase was successfully and error-free completed before continuing to mitosis.
· Damage Inspection: Much like the G1 checkpoint, the cell examines its DNA for possible S phase-related damage.
· Checkpoint proteins: Cyclins and CDKs also play important functions in the G2 checkpoint, according to checkpoint proteins. DNA integrity and replication completion are monitored by certain cyclin-CDK complexes.
· Decision Point: If the DNA is unharmed and the cell is ready to begin mitosis, the cell enters the mitotic phase (M phase). The cell may start DNA repair processes or go through apoptosis (programmed cell death) if any problems are found.
3) Mitotic Checkpoint (Spindle Checkpoint):
· Chromosome Alignment: The mitotic checkpoint is activated when the chromosomes line up along the equator of the cell during the metaphase of mitosis. It guarantees that each chromosome is accurately aligned and connected to spindle fibres.
· Evaluation of Attachment: The centromeres of chromosomes contain specialized proteins termed kinetochores, which are checked for correct attachment to spindle fibres. Aneuploidy, in which daughter cells have an incorrect amount of chromosomes, can result from improper attachments.
· Checkpoint Proteins: Essential elements of the mitotic checkpoint are the proteins Mad1, BUB1, and BUB3.
· Decision point: The cell moves on to the final phases of mitosis if all chromosomes are appropriately connected and aligned. The checkpoint, however, stops mitosis if attachment faults are discovered and waits for them to be fixed. It prevents the unequal distribution of chromosomes into daughter cells promoting genetic stability.
Dysfunction of checkpoints
Dysfunction
of cell cycle checkpoints can lead to various diseases, with cancer being one
of the most prominent examples. When these checkpoints fail to function
properly, cells can divide uncontrollably, accumulate mutations, and give rise
to tumors. Here are some key diseases and conditions associated with
dysfunction in cell cycle checkpoints:
1) Cancer:
• Uncontrolled
Cell Division: Loss of control over cell cycle checkpoints is one of the
characteristics of cancer. Cells may avoid these checkpoints and continue to
divide if certain genes controlling them are altered or mutated.
• Tumor
Formation: Tumors are collections of rapidly dividing cells that can
develop as a result of malfunctioning checkpoints. Cells may begin the cell
cycle without performing adequate checks for DNA damage or food supply if the
G1 checkpoint fails, allowing injured cells to proliferate.
• Metastasis:
Because cells with DNA damage or aberrant chromosome counts can elude detection
and travel to different parts of the body, defective checkpoints can also
contribute to metastasis, the spread of cancer from one organ or tissue to
others.
2) Genetic disease
• Genomic
Instability Syndromes: Disorders of cell cycle checkpoints, including
ataxia-telangiectasia and Fanconi anaemia, can cause genomic instability syndromes.
A higher risk of cancer and weakened DNA repair pathways characterise these
diseases.
3) Neurogenerative
Diseases:
• Alzheimer:
Neurodegenerative disorders like Alzheimer's have been linked to the cell
cycle, according to research. Neuronal cell death and cognitive deterioration
may be influenced by dysfunctional cell cycle control in neurons.
4) Autoimmune Disease:
• Systemic
Lupus Erythematosus (SLE): SLE is an autoimmune condition in which the
body's immune system assaults healthy cells and tissues. Autoantibodies against
one's own antigens can be produced as a result of dysregulated cell cycle
checkpoints, which adds to the pathophysiology of the illness.
5) Premature aging
Syndromes:
• Progeria (Hutchinson-Gilford Progeria Syndrome): It is a rare hereditary condition that causes young people to age more quickly. In people with progeria, malfunctioning cell cycle checkpoints are one of the things that cause them to age too soon.
6) Immunodeficiency Disorders:
• Severe
Combined Immunodeficiency (SCID): The growth of immune cells can be
hampered by dysfunction in cell cycle checkpoints, which can result in severe
immunodeficiency diseases like severe combined immunodeficiency (SCID).
Due to the
understanding developed into the functioning of checkpoints in the cell cycle,
there are various targeted medicines developed disorders. For instance, several
cancer therapies target checkpoint proteins directly to prevent the unchecked
division of cancer cells.
Studies on checkpoint dysfunction in various
diseases provide insights into biology and potential therapies.
