2. Signaling Pathways
  3. Cell Cycle/DNA Damage

Cell Cycle/DNA Damage (细胞周期/DNA 损伤)

Cell Cycle/DNA Damage 相关靶点 (followed by the number of products) :

Cell Cycle

DNA Damage

Unfolded Protein Response

Cell Cycle/DNA Damage Cell Cycle/DNA Damage
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Overview of Cell Cycle/DNA Damage:

Cell Cycle includes many processes necessary for successful self-replication, and consists of DNA synthesis (S) and mitosis (M) phases separated by gap phases in the order G1–S–G2–M. S phase and M phase are usually separated by gap phases called G1 and G2, when cell-cycle progression can be regulated by various intracellular and extracellular signals. In order to move from one phase of its life cycle to the next, a cell must pass through numerous checkpoints. At each checkpoint, specialized proteins determine whether the necessary conditions exist. Progression through G1 phase is controlled by pRB proteins, and phosphorylation of pRB proteins by CDKs releases E2F factors, promoting the transition to S phase. The G2/M transition that commits cells to division is a default consequence of initiating the cell cycle at the G1/S transition, many proteins, such Wee1, PLK1 and cdc25, is involved the regulation of this process. The best-understood checkpoints are those activated by DNA damage and problems with DNA replication.

DNA damage response (DDR) is a series of regulatory events including DNA damage, cell-cycle arrest, regulation of DNA replication, and repair or bypass of DNA damage to ensure the maintenance of genomic stability and cell viability. Genome instability arises if cells initiate mitosis when chromosomes are only partially replicated or are damaged by a double-strand DNA break (DSB). To prevent cells with damaged DNA from entering mitosis, ATR inhibits cyclin B/Cdk1 activation by stimulating the Cdk1 inhibitory kinase Wee1 and inhibiting Cdc25C via Chk1, besides, ATM and ATR also initiate DNA repair by phosphorylating several other substrates.

In cancer cells, the cell cycle regulators as well as other elements of the DDR pathway have been found to protect tumor cells from different stresses and to promote tumor progression. Thus, cell cycle proteins that directly regulate cell cycle progression (such as CDKs), as well as checkpoint kinases, Aurora kinases and PLKs, are promising targets in cancer therapy.

 

参考文献:

[1] Rhind N, et al. Cold Spring Harb Perspect Biol. 2012 Oct; 4(10): a005942.

[2] Duronio RJ, et al. Cold Spring Harb Perspect Biol. 2013 Mar; 5(3): a008904.

[3] Liu W, et al. Mol Cancer. 2017 Mar 14;16(1):60.

[4] Ghelli Luserna di Rora' A, et al. J Hematol Oncol. 2017 Mar 29;10(1):77.

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