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.
Introduction
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 G1 checkpoint, at the G1/S transition.
The G2 checkpoint, at the G2/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 G1 checkpoint
The G1 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 G1 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 G1 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
Nutrients
Growth factors
DNA damage
At the G1 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 G1 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 1
checkpoint, it may leave the cell cycle and enter a resting
state called G0 phase. Some cells stay permanently in G0,
while others resume dividing if conditions improve.
The G2 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 G2 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 2
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.
