Chk1 (checkpoint kinase 1, Chk1) is a member of the serine/threonine protein kinase family and is the core protein of the cell cycle checkpoint in DNA damage response (DDR). Many studies have shown that Chk1 protein kinase has the function of promoting tumor cell proliferation. The lack of CHK1 protein kinase can make tumor cells more sensitive to radiotherapy or chemotherapy, and its inhibitors combined with other molecular targeted drugs have a "synthetic lethal" effect, so Chk1 could serve as a new target for future tumor treatment.
Figure 1. Protein structure of Chk1.
Functions
Checkpoint kinases (Chks) are protein kinases involved in cell cycle control. Two checkpoint kinase subtypes have been identified: Chk1 and Chk2. Chk1 is an important component of the genome surveillance pathway and a key regulator of cell cycle and cell survival. Chk1 is required to initiate DNA damage checkpoints and has recently been shown to play a role in the normal (undisturbed) cell cycle. Chk1 affects all phases of the cell cycle, including S phase, G2 / M transition and M phase. In addition to mediating cell cycle checkpoints, Chk1 also helps DNA repair processes, gene transcription, embryonic development, and cell-to-HIV Infection and somatic response.
Structure of Chk1 protein kinase
The human Chk1 gene is located on chromosome 11q24 and encodes a protein kinase containing 476 amino acids and a molecular weight of 54 kD. It is highly conserved in evolution and widely exists in eukaryotic cells. It was originally found in fission yeast. It includes Four domains: N-terminal kinase domain, variable linker domain, SQ/TQ regulatory domain, and C-terminal inhibitory domain. Chk1 protein kinase is a major regulator of cell cycle, cell survival, and embryogenesis. In the normal cell cycle, the Chk1 protein kinase regulates S-phase DNA replication, entry of the G2/M transition and mitosis, and spindle checkpoints in the M phase. In addition, Chk1 protein kinase also regulates the stress and heat shock response of cells to HIV infection, oxygen exposure, protein misfolding, etc.
Chk1 protein kinase and cell cycle
The cell cycle consists of a series of highly ordered and continuous phases that ultimately divide and proliferate cells. A significant feature of it is its phase sequence, that is, the cell cycle starts and enters the next phase after the previous phase is completed. This feature is monitored by the cell cycle regulatory mechanism, and its core component is the cell cycle-dependent protein kinase (cyclin-dependent kinase, CDKs). CDKs rely on the specific or phasic expression, accumulation, and breakdown of cyclins to control the cell cycle process. CDKs and cyclins combine to form a mitosis promoting factor (MPF), which regulates the initiation and progress of various links in the cell cycle. CDKs are the catalytic subunits of MPF, and cyclins are the regulatory subunits of MPF. Cdc25 family phosphatases can dephosphorylate and activate CDK1, thereby promoting the cell cycle; Wee1 protein kinase can phosphorylate and inhibit the activity of CDK1, so that the cell cycle is blocked in the G2 phase; PLK1 (polo like kinase 1, PLK1) is a mitotic kinase, Involved in centrosome maturation, spindle formation and cytoplasmic separation, it can phosphorylate Wee1 and degrade it, leading to CDK1 activation and mitotic entry.
Chk1 protein kinase inhibitor
Chk1 protein kinase inhibitors (Figure 2) include ATP-competitive inhibitors and non-ATP-competitive inhibitors. The former inhibits kinase activity through targeted binding to the ATP-binding hinge region of Chk1 protein kinase, and the latter is at the allosteric site of Chk1 protein kinase. Chk1 protein kinase inhibitors are divided into seven categories based on their chemical structure, including pyrrolocarbazolones, indoles, quinolinones, indenopyrazoles, ureas, sulfur compounds, and some other types.
Conclusions
Chk1 protein kinase plays a vital role in cell cycle regulation and DNA damage response. In the normal cell cycle, the Chk1 protein kinase regulates the entry of G1/S transition, S, and mitosis. In DDR, the Chk1 protein kinase is an important signal sensor and a trigger for G2 checkpoint activation. Significant advances in Chk1 protein kinase's potential as cancer treatment targets in cancer treatment.
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