Checkpoints and regulators

Cdks, cyclins, and the APC/C are direct regulators of cell cycle transitions, but they aren’t always in the driver’s seat. Instead, they respond to cues from inside and outside the cell. These cues influence activity of the core regulators to determine whether the cell moves forward in the cell cycle. Positive cues, like growth factors, typically increase activity of Cdks and cyclins, while negative ones, like DNA damage, typically decrease or block activity.
As an example, let's examine how DNA damage halts the cell cycle in Gstart subscript, 1, end subscript. DNA damage can, and will, happen in many cells of the body during a person’s lifetime (for example, due to UV rays from the sun). Cells must be able to deal with this damage, fixing it if possible and preventing cell division if not. Key to the DNA damage response is a protein called p53, a famous tumor suppressor often described as “the guardian of the genome.” start superscript, 10, end superscript
p53 works on multiple levels to ensure that cells do not pass on their damaged DNA through cell divisionstart superscript, 3, end superscript. First, it stops the cell cycle at the Gstart subscript, 1, end subscript checkpoint by triggering production of Cdk inhibitor (CKI) proteins. The CKI proteins bind to Cdk-cyclin complexes and block their activity (see diagram below), buying time for DNA repair. p53's second job is to activate DNA repair enzymes. If DNA damage is not fixable, p53 will play its third and final role: triggering programmed cell death so damaged DNA is not passed on.
Simplified diagram of how p53 halts the cell cycle at the G1/S checkpoint. p53 is activated by DNA damage and causes production of a Cdk inhibitor, which binds to the Cdk-G1/S cyclin complex and inactivates it. This halts the cell in G1 and prevents it from entering S phase, allowing time for the DNA damage to be fixed.
By ensuring that cells don't divide when their DNA is damaged, p53 prevents mutations (changes in DNA) from being passed on to daughter cells. When p53 is defective or missing, mutations can accumulate quickly, potentially leading to cancer. Indeed, out of all the entire human genome, p53 is the single gene most often mutated in cancers.start superscript, 11, end superscript p53 and cell cycle regulation are key topics of study for researchers working on new treatments for cancer.

Comments

Post a Comment

Popular posts from this blog

Cell Cycle Regulation

Image
In the article on cell cycle checkpoints, we looked at the  why  of cell cycle transitions: the factors that a cell considers when deciding whether or not to move forward through the cell cycle. These include both external cues (like molecular signals) and internal cues (like DNA damage). Cues like these act by changing the activity of core cell cycle regulators inside the cell. These core cell cycle regulators can cause key events, such as DNA replication or chromosome separation, to take place. They also make sure that cell cycle events they take place in the right order and that one phase (such as G _1 ​ 1 ​ ​ start subscript, 1, end subscript ) triggers the onset of the next phase (such as S). In this article, we'll look at a few of the most important core cell cycle regulators: proteins called cyclins, enzymes called Cdks, and an enzyme complex called the APC/C. Cyclins Cyclins  are among the most important core cell cycle regulators. Cyclins are a group of
Read more

The anaphase-promoting complex

Image
In addition to driving the events of M phase, MPF also triggers its own destruction by activating the  anaphase-promoting complex/cyclosome  ( APC/C ), a protein complex that causes M cyclins to be destroyed starting in anaphase. The destruction of M cyclins pushes the cell out of mitosis, allowing the new daughter cells to enter G _1 ​ 1 ​ ​ start subscript, 1, end subscript . The APC/C also causes destruction of the proteins that hold the sister chromatids together, allowing them to separate in anaphase and move to opposite poles of the cell. How does the APC/C do its job? Like a Cdk, the APC/C is an enzyme, but it has different type of function than a Cdk. Rather than attaching a phosphate group to its targets, it adds a small protein tag called  ubiquitin  ( Ub ). When a target is tagged with ubiquitin, it is sent to the  proteasome , which can be thought of as the recycle bin of the cell, and destroyed. For example, the APC/C attaches a ubiquitin tag to M cyclins, causing t
Read more