File:Current and potential targeting strategies in association with the cell cycle.png
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[edit]DescriptionCurrent and potential targeting strategies in association with the cell cycle.png |
English: Shown here are two major checkpoints, G1/S and G2/M. The G2/M checkpoint is crucial to induce cell cycle arrest and allow the cell to repair DNA defects before it enters M phase. Both checkpoints, however, can be inhibited by CDKs which facilitate cell cycle progression regardless of the DNA defects. Theoretically, if the cell is allowed to enter mitosis without DNA damage properly fixed, cell death could happen due to mitotic catastrophe. Therefore, in the setting of replicative stress, approaches facilitating cell cycle progression through G2-M, such as activating CDKs or reducing the inhibitory effect on CDKs could have a cell killing effect. DNA damage will result in both DSBs and ssDNA/SSBs, with the latter as the major cause of replicative stress. ssDNA/SSBs activate ATR-Chk1 signaling, which in turn activates tumor suppressors p53 and p21 and inhibits CDKs. ssDNA/SSBs may also activate PARP which in turn enhances Chk1 activity. Wee1 can directly inhibit CDKs. Therefore, inhibitors of PARP, ATR, Chk1 and Wee1 will all activate CDKs and allow the cell to enter mitosis despite the presence of unrepaired DNA. If SSBs are not fixed, they may become secondary DSBs, therefore targeting DSB-induced DNA repair mechanisms could also be a promising strategy. DSBs activate the tumor suppressor BRCA as well as ATM-Chk2 signaling and DNA-PK. Chk2 also activates p53. Therefore, it is not surprising that inhibition of ATR-Chk1 could be particularly useful for p53 deficient tumors, and PARP inhibition for patients with BRCA mutation. (DSBs: Double strand breaks; SSBs: Single strand breaks; DNA-PK: DNA-dependent protein kinase; CDK: Cyclin-dependent kinase).[1] |
Date | |
Source | https://doi.org/10.3390/genes7080051 |
Author | Jun Zhang, Qun Dai, Dongkyoo Park, and Xingming Deng |
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current | 22:36, 24 May 2020 | 2,200 × 1,500 (1.1 MB) | Rob Hurt (talk | contribs) | Uploaded a work by Jun Zhang, Qun Dai, Dongkyoo Park, and Xingming Deng from https://doi.org/10.3390/genes7080051 with UploadWizard |
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File change date and time | 08:31, 24 May 2020 |
Date metadata was last modified | 08:31, 24 May 2020 |
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