The checkpoints of the cell cycle are several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be paused until conditions are favorable. Mistakes in the duplication or distribution of the chromosomes lead to mutations that may be passed forward to every new cell produced from an abnormal cell.
These checkpoints occur near the end of G1, at the G2/M transition, and during metaphase.
The G1 checkpoint determines whether all conditions are favorable for cell division to proceed. The G1 checkpoint, also called the restriction point. Cell size, growth factors, and integrity of DNA play a major role in helping cell past G1 checkpoint. A cell that does not meet all the requirements will not progress to the S phase.
The cycle halts or cell goes to G0 (inactive) phase and await further signals when conditions become favorable. If a cell meets the requirements for the G1 checkpoint, the cell will enter S phase and begin DNA replication. Cyclins and cyclin-dependent kinases (CDKs) play an important role in signaling the cell to move further into S phase
The most important role of G2 checkpoint is to ensure that all of the chromosomes have been accurately replicated without any mistakes or damage. If any problem is detected with the DNA, cell cycle is paused. The cell attempts to either complete DNA replication or repair the damaged DNA. If DNA is replicated properly and/or there is no damage, cyclin-dependent kinases (CDKs) signal the beginning of mitotic cell division.
The M checkpoint occurs near the end of metaphase stage of mitosis. This checkpoint is also known as the spindle checkpoint because it determines whether all the sister chromatids are correctly attached to the spindle microtubules.
Defects of checkpoints and cell fate
Depending on the severity of the cell cycle defect, checkpoint dysfunction can result in outcomes ranging from cell death to cell cycle reprogramming that causes cancer.
The cell cycle is controlled by proteins in the cytoplasm (Figure 4). In animal cells the ones that play major roles are listed below:
Cyclin-dependent kinases (Cdks)
They are regulatory proteins that belong to the family of serine/threonine protein kinases and regulate progress of cell cycle. They get activated at specific points of the cell cycle. CDks consist of a catalytic subunit with a low intrinsic enzymatic activity and a regulatory subunit called cyclin. Cdk level remains constant during the cell cycle.
- G1 Cdk (Cdk4)
- S-phase Cdk (Cdk2)
- M-phase Cdk (Cdk1)
Cyclins and their associated cyclin-dependent kinases (CDKs) are the key regulators of the cell cycle, whereas specific transitions in the cell cycle are controlled solely by specific CDKs
- G1 cyclins (D cyclins)
- S-phase cyclins (cyclins E and A)
- mitotic cyclins (B cyclins)
In higher organisms, the transcription factor p53 is a critical component of DNA damage checkpoints, particularly in G1 phase. It is also known as the guardian of genome orTP53 (tumor protein), a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression. It is very important for cells in multicellular organisms to suppress cancer. In human it is located on chromosome 17.
The p53 protein is a phosphoprotein made of 393 amino acids. It consists of four units (or domains), performing separate functions. These are shown below:
- Activation of transcription factors
- Recognition of specific DNA sequences (core domain)
- Tetramerization of protein
- Recognition of damaged DNA (misaligned base pairs or single-stranded DNA)
It is cyclin dependent kinase inhibitor (CK1). Production of p21 is triggered by p53. p21 pauses the cell cycle by binding to and inhibiting the activity of Cdk/cyclin complex.
Retinoblastoma-associated protein (RB1, also known as RB) regulates cell proliferation through the transcriptional repression of genes involved in cellular G1 to S phase transition. RB also plays roles in the cell cycle, maintenance of genome stability, and apoptosis.
The anaphase-promoting complex (APC)
It is also called cyclosome. APC triggers the events that lead to destruction of cohesion, allowing sister chromatids to separate and degrade the mitotic (B) cyclins.