regulation of DNA damage checkpoint

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of a DNA damage checkpoint. [GOC:obol]

The DNA damage checkpoint is a complex cellular surveillance system that ensures the integrity of the genome by halting cell cycle progression in response to DNA damage. This intricate process involves a cascade of events orchestrated by a network of proteins that recognize DNA damage, signal its presence, and activate downstream effectors to repair the damage or, if irreparable, trigger apoptosis.

The process begins with the detection of DNA damage by sensor proteins. These proteins, such as ATM (Ataxia-Telangiectasia Mutated) and ATR (ATM and Rad3-related), are activated upon sensing double-strand breaks (DSBs) or single-strand breaks (SSBs), respectively. Once activated, these kinases initiate a signaling cascade by phosphorylating downstream effector proteins.

One of the key downstream targets of ATM and ATR is the checkpoint kinase 1 (CHK1) and checkpoint kinase 2 (CHK2). Phosphorylation of CHK1 and CHK2 by ATM and ATR, respectively, leads to their activation. Activated CHK1 and CHK2 then phosphorylate a multitude of substrates, including the CDC25 phosphatases, which are essential for cell cycle progression. Phosphorylation of CDC25 by CHK1 and CHK2 inhibits their activity, effectively blocking the dephosphorylation of key cell cycle regulators like cyclin-dependent kinases (CDKs). This inhibition of CDC25 activity prevents the activation of CDKs, thereby halting the cell cycle at various checkpoints.

The DNA damage checkpoint not only pauses the cell cycle but also initiates DNA repair mechanisms. Activated ATM and ATR trigger the recruitment of DNA repair proteins to the site of damage, facilitating the repair of DSBs and SSBs through homologous recombination or non-homologous end-joining pathways.

In the event of irreparable DNA damage, the DNA damage checkpoint can trigger apoptosis, a programmed cell death pathway that eliminates damaged cells and prevents the propagation of mutations. This apoptotic response is often mediated by the activation of p53, a tumor suppressor protein that plays a crucial role in maintaining genomic stability.

The DNA damage checkpoint is a fundamental cellular process that safeguards the integrity of the genome. It is a tightly regulated system with multiple layers of control, ensuring that DNA damage is properly detected, signaled, repaired, or if irreparable, eliminated. This intricate network of proteins and their interactions ensures the accurate replication and transmission of genetic information, preventing the accumulation of mutations and the development of cancer.'
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Proteins (5)

Compounds (7)