Cell cycle checkpoints
How cells use checkpoints at the end of G1 phase, end of G2 phase, and partway through M phase (the spindle checkpoint) to regulate the cell cycle.
As cells move through the cell cycle, do they breeze through from one phase to the next? If they're cancer cells, the answer might be yes. Normal cells, however, move through the cell cycle in a regulated way. They use information about their own internal state and cues from the environment around them to decide whether to proceed with cell division. This regulation makes sure that cells don't divide under unfavorable conditions (for instance, when their DNA is damaged, or when there isn't room for more cells in a tissue or organ).
Cell cycle checkpoints
A checkpoint is a stage in the eukaryotic cell cycle at which the cell examines internal and external cues and "decides" whether or not to move forward with division.
There are a number of checkpoints, but the three most important ones are:
- The G checkpoint, at the G/S transition.
- The G checkpoint, at the G/M transition.
- The spindle checkpoint, at the transition from metaphase to anaphase.
Diagram of cell cycle with checkpoints marked. G1 checkpoint is near the end of G1 (close to the G1/S transition). G2 checkpoint is near the end of G2 (close to the G2/M transition). Spindle checkpoint is partway through M phase, and more specifically, at the metaphase/anaphase transition.
The G checkpoint
The G checkpoint is the main decision point for a cell – that is, the primary point at which it must choose whether or not to divide. Once the cell passes the G checkpoint and enters S phase, it becomes irreversibly committed to division. That is, barring unexpected problems, such as DNA damage or replication errors, a cell that passes the G checkpoint will continue the rest of the way through the cell cycle and produce two daughter cells.
The G1 checkpoint. The G1 checkpoint is located at the end of G1 phase, before the transition to S phase. If cells don't pass the G1 checkpoint, they may "loop out" of the cell cycle and into a resting state called G0, from which they may subsequently re-enter G1 under the appropriate conditions.
At the G1 checkpoint, cells decide whether or not to proceed with division based on factors such as:
- Cell size
- Growth factors
- DNA damage
At the G checkpoint, a cell checks whether internal and external conditions are right for division. Here are some of the factors a cell might assess:
- Size. Is the cell large enough to divide?
- Nutrients. Does the cell have enough energy reserves or available nutrients to divide?
- Molecular signals. Is the cell receiving positive cues (such as growth factors) from neighbors?
- DNA integrity. Is any of the DNA damaged?
These are not the only factors that can affect progression through the G checkpoint, and which factors are most important depend on the type of cell. For instance, some cells also need mechanical cues (such as being attached to a supportive network called the extracellular matrix) in order to divide.
If a cell doesn’t get the go-ahead cues it needs at the G checkpoint, it may leave the cell cycle and enter a resting state called G phase. Some cells stay permanently in G, while others resume dividing if conditions improve.
The G checkpoint
Image of the cell cycle with the G2 checkpoint marked. At the G2 checkpoint, the cell checks for:
- DNA damage
- DNA replication completeness
To make sure that cell division goes smoothly (produces healthy daughter cells with complete, undamaged DNA), the cell has an additional checkpoint before M phase, called the G checkpoint. At this stage, the cell will check:
- DNA integrity. Is any of the DNA damaged?
- DNA replication. Was the DNA completely copied during S phase?
If errors or damage are detected, the cell will pause at the G checkpoint to allow for repairs. 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 damage is irreparable, the cell may undergo apoptosis, or programmed cell death. This self-destruction mechanism ensures that damaged DNA is not passed on to daughter cells and is important in preventing cancer.
The spindle checkpoint
Image of the cell cycle with the spindle checkpoint marked. At the spindle checkpoint, the cell checks for:
- Chromosome attachment to spindle at the metaphase plate
The M checkpoint is also known as the spindle checkpoint: here, the cell examines whether all the sister chromatids are correctly attached to the spindle microtubules. Because the separation of the sister chromatids during anaphase is an irreversible step, the cycle will not proceed until all the chromosomes are firmly attached to at least two spindle fibers from opposite poles of the cell.
How does this checkpoint work? It seems that cells don't actually scan the metaphase plate to confirm that all of the chromosomes are there. Instead, they look for "straggler" chromosomes that are in the wrong place (e.g., floating around in the cytoplasm). If a chromosome is misplaced, the cell will pause mitosis, allowing time for the spindle to capture the stray chromosome.
How do the checkpoints actually work?
This article gives a high-level overview of cell cycle control, outlining the factors that influence a cell’s decision to pause or progress at each checkpoint. However, you may be wondering what these factors actually do to the cell, or change inside of it, to cause (or block) progression from one phase of the cell cycle to the next.
The general answer is that internal and external cues trigger signaling pathways inside the cell that activate, or inactivate, a set of core proteins that move the cell cycle forward. You can learn more about these proteins, and see examples of how they are affected by cues such as DNA damage, in the article on cell cycle regulators.
Want to join the conversation?
- If cells who have broken DNA automatically die, then would it be possible for a chemical to be given to cancer patients, that would break or make the infected cells think their DNA was broken? Wouldn't this kill out the cancer?(12 votes)
- There are many repair processes for DNA breaks — for KhanAcademy material on this see:
Consequently, it is unlikely for a single break to kill a cell.
That being said, radiation treatment and (most?) chemotherapy drugs do exactly what you are suggesting — they cause large amounts of DNA damage and overwhelm the ability of rapidly dividing cells§ to repair themselves.
This usually leads to cell death.
§This includes the cancer cells we want to kill, but also many healthy cells including those renewing the lining of the gut and in hair follicles. Killing of healthy cells is a big part of why people undergoing cancer treatment often feel very ill and lose their hair.(26 votes)
- what happens to a cell if it does not “pass” the spindle checkpoint?(6 votes)
- In this case, the cell would not continue past metaphase, rather wait until the spindle fibers have all attached to the sister chromatids. If the fibers have still missed some chromatids, then either the cell will divide incorrectly with unequal genetic material in the daughter cells or it will have the proper checks in place to initiate cell death.(10 votes)
- Do the same checkpoints exist in meiosis? Thank you!(8 votes)
- Good question!
Yes, recent research has shown that regulation of meiosis is similar to that of mitosis (though somewhat more complicated).
References and further reading:
- why would damage to a cell's DNA prevent it from doing it's job?(4 votes)
- The DNA is sort of like the instructions for building, operating, and maintaining a cell. If those instructions get damaged then things start to go wrong.
Maybe this analogy will help?
Imagine you were trying to build a model by following written instructions. Part way through you discover that something has damaged a section of the instructions. You do your best, but at the end your project ends up being a bit messed up.
Then someone makes a photocopy of your damaged directions, which end up even less clear than your original. They then try to build another copy of the model, which ends up even more flawed than your version ...
Does any of that help?(12 votes)
- what happens if cells don't divide(2 votes)
- It will kill itself if it can't fix itself. Cell suicide is called apoptosis.(3 votes)
- If there are checkpoints, then why are there still people with extra/missing chromosomes because the spindles do not attach/do their job (e.g. down syndrome)?(2 votes)
- Alright well the most common form of down syndrome is known as trisomy 21, which is when a person has 47 chromosomes instead of 46 chromosomes in each cell. This is caused by nondisjunction, which gives a gamete an extra copy of chromosome 21. Nondisjunction would occur at the spindle checkpoint, and so the cell is supposed to be stopped and the error corrected there. However, if the spindle checkpoint isn't working properly, nondisjunction can occur and the cell will go on with the division even with that error present, resulting in conditions such as trisomy 23.(8 votes)
- How many strategies are there to increase the activity of checkpoints? I think it will be a great hypothesis for anticancer drug design.(3 votes)
- Quite interesting!
I found an article explaining the therapeutic potential and short backs of that approach. It turns out that targeting cell checkpoints may be a double-edge sword for cancer.
DNA- and mitotic spindle-damaging drugs are even mainstream in cancer therapy. While there is no something to 'increase' activity, there are things which target and damage points.
Actually, drugs are inhibitors for checkpoints so it automatically leads to apoptosis.
The drawback is that these inhibitors don't work in all types of tumors.(5 votes)
- For each of the three main checkpoints in the cell cycle, indicates what could happen if the checkpoint didn't function?(4 votes)
- Do the lines in the diagrams symbolize where in the cycle the checkpoint is occurring? If so, isn't the G1 Checkpoint supposed to occur before the G0 Phase?(2 votes)
- No, because that would mean the cell passed the checkpoint. In other words, the cell is stopped before passing the line/ the checkpoint. Think of it sort of as luggage checking at an airport, so like making sure the cell has what it's supposed to have and nothing else before letting it pass, otherwise it goes to G0 phase.(5 votes)
- So G1 and G2 checkpoints both check for cell damage?(2 votes)
- G1 mainly focuses on metabolically active, but in the short answer, yes.(3 votes)