mitotic intra-S DNA damage checkpoint signaling

Definition

Target type: biologicalprocess

A mitotic cell cycle checkpoint that slows DNA synthesis in response to DNA damage by the prevention of new origin firing and the stabilization of slow replication fork progression. [GOC:vw]

The mitotic intra-S DNA damage checkpoint, a critical component of the cellular stress response, is activated upon DNA damage during the S phase of the cell cycle. Its primary function is to prevent cells from entering mitosis with unrepaired DNA damage, thus ensuring genomic integrity. This checkpoint is activated by a cascade of events initiated by the recognition of DNA damage by sensor proteins. These sensors, including ATR (ATM and Rad3-related), activate downstream signaling pathways that involve the checkpoint kinases Chk1 and Chk2.

Upon sensing DNA damage, ATR is recruited to the site of damage and phosphorylates a key effector molecule, the single-stranded DNA binding protein RPA. Phosphorylated RPA then serves as a platform for the recruitment of the checkpoint kinase ATRIP. This complex further activates ATR, which in turn phosphorylates the checkpoint kinase Chk1. Phosphorylation of Chk1 by ATR leads to the activation of Chk1, which then plays a crucial role in arresting the cell cycle at the G2/M transition.

Chk1 primarily targets the Cdc25 family of phosphatases, which are essential for activating the cyclin B-Cdk1 complex, the key regulator of the G2/M transition. By phosphorylating Cdc25, Chk1 inhibits its activity, preventing the activation of cyclin B-Cdk1 and thus delaying the entry into mitosis.

In addition to inhibiting Cdc25, Chk1 also activates the Wee1 kinase, another critical regulator of the G2/M transition. Wee1 phosphorylates Cdk1, further preventing its activation and promoting cell cycle arrest.

The mitotic intra-S DNA damage checkpoint also involves other signaling pathways, including the ATM-Chk2 pathway. ATM, another DNA damage sensor, is activated upon double-strand DNA breaks and subsequently phosphorylates Chk2. Activated Chk2 contributes to the checkpoint response by inhibiting Cdc25 and activating p53, a transcription factor involved in DNA repair and apoptosis.

The mitotic intra-S DNA damage checkpoint ensures that DNA damage is repaired before the cell enters mitosis. This checkpoint delay provides time for DNA repair mechanisms to function, minimizing the risk of transmitting damaged DNA to daughter cells. Failure of this checkpoint can lead to genomic instability and increased susceptibility to cancer. The checkpoint is a complex and tightly regulated process that involves multiple proteins and signaling pathways, all working in concert to maintain genomic integrity.'
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Proteins (2)

Compounds (82)