What activates Chk1?
Chk1 activation involves phosphorylation at conserved sites. Upon activation, Chk1 phosphorylates a variety of substrate proteins, resulting in the activation of DNA damage checkpoints, cell cycle arrest, DNA repair, and/or cell death.
What phosphorylates Chk1?
In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. We demonstrate that Chk1 phosphorylation by ATR is antagonized by protein phosphatase 2A (PP2A).
Does ATR phosphorylate Chk1?
Chk1 is phosphorylated on S345 after DNA damage and this is regulated by Atr. (A) Phosphorylation of Chk1 on S345 after DNA damage. 293T cells were untreated or treated with IR (20 Gy and harvested after 1 hr), UV (50 J/m2 and harvested after 2 hr) or HU (1 mm for 24 hr).
What does phosphorylation do in the cell cycle?
Summary. Protein phosphorylation is a common way to regulate signaling pathways in the cell cycle. Kinases catalyze phosphoryl transfer from ATP to substrates and change downstream protein-protein interaction in such way that a signaling pathway is either switched on or shut off.
What is ATR Chk1?
The cell cycle checkpoint proteins ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) and its major downstream effector checkpoint kinase 1 (CHK1) prevent the entry of cells with damaged or incompletely replicated DNA into mitosis when the cells are challenged by DNA damaging agents, such as radiation therapy …
Why is phosphorylation important in mitosis?
During mitosis, phosphorylation of chromosome-associated proteins is a key regulatory mechanism. Mass spectrometry has been successfully applied to determine the complete protein composition of mitotic chromosomes, but not to identify post-translational modifications.
Where does phosphorylation occur in the cell cycle?
For example, at the beginning of S phase, S-CDK catalyzes phosphorylation of the proteins that initiate DNA replication by allowing DNA replication complexes to form. Later, during mitosis, M-CDKs phosphorylate a wide range of proteins.
What is the Chk1 gene?
Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response.
Is Chk1 a tumor suppressor?
Further, emerging evidence suggests that Chk1 does not appear to be a tumor suppressor; instead, it promotes tumor growth and may contribute to anticancer therapy resistance.
What is an ATR inhibitor?
It is an ATR inhibitor, a promising class of new drugs that target the ATR (ataxia telangiectasia mutated and Rad3-related) kinase, which is involved in DNA damage repair. The drug inhibits the growth of tumor cells by limiting their ability to repair damaged DNA.
What is the function of phosphorylated protein?
Protein phosphorylation is a reversible post-translational modification of proteins. In eukaryotes, protein phosphorylation functions in cell signaling, gene expression, and differentiation.
Is ATR required for phosphorylation of Chk1 and cell cycle regulation?
Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev.14:2745-2756.
What happens when Chk1 is activated?
Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle. In 1993, Beach and associates initially identified Chk1 as a serine/threonine kinase which regulates the G2/M phase transition in fission yeast.
Why is it important to prevent Chk1 from being phosphorylated?
Since Chk1 phosphorylation functions as a trigger to release the intra-molecular restraint, preventing Chk1 from being phosphorylated by ATR is important to maintain Chk1 in the ‘closed’ inactive conformation under normal growth conditions.
Where is Chk1 located on chromosome 11?
Human Chk1 is located on chromosome 11 on the cytogenic band 11q22-23. Chk1 has a N-terminal kinase domain, a linker region, a regulatory SQ/TQ domain and a C-terminal domain. Chk1 contains four Ser/Gln residues. Chk 1 activation occurs primarily through the phosphorylation of the conserved sites, Ser-317, Ser-345 and less often at Ser-366.