RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage
Cell cycle checkpoint controls at the G1 to S transition and the G2 to M transition prevent the cell cycle from progressing when DNA is damaged. The ATM protein kinase detects DNA damage and in response to this activates DNA repair factors and inhibits cell cycle progression. Two of the proteins that ATM phosphorylates in response to DNA damage are the tumor suppressor p53 and the checkpoint kinase chk1. In turn, the tumor suppressor p53 interacts with p21 to block the activity of cdk2 (cyclin dependent kinase 2) preventing passage from G1 to S phase and harmful replication of damaged DNA. One of the targets of cdk2 is the Rb gene product, another tumor suppressor. When dephosphorylated, Rb interacts with E2F transcription factors and prevents transcription of genes required for progression through the cell cycle. When phosphorylated by cell cycle dependent kinases like cdk2 and cdk4, Rb no longer interacts with E2F and the cell cycle proceeds through the G1-S checkpoint (see 'Cyclins and Cell Cycle Regulation' pathway and 'Cell Cycle: G1/S Check Point' pathway). DNA damage also regulates the G2-M phase transition by acting on the cell cycle regulator cdc2 (See 'cdc25 and chk1 Regulatory Pathway in response to DNA damage').
Contributor: Cell Signaling Technology, Glenn Croston, PhD
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