Signaling Pathway

Cell Cycle/DNA Damage

Cell Cycle/DNA Damage

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DNA is prone to numerous forms of damage that can injure cells and impair fitness. Cells have evolved an array of mechanisms to repair these injuries. Proliferating cells are especially vulnerable to DNA damage due to the added demands of cellular growth and division. Cell cycle checkpoints represent integral components of DNA repair that coordinate cooperation between the machinery of the cell cycle and several biochemical pathways that respond to damage and restore DNA structure. By delaying progression through the cell cycle, checkpoints provide more time for repair before the critical phases of DNA replication, when the genome is replicated, and of mitosis, when the genome is segregated. Loss or attenuation of checkpoint function may increase spontaneous and induced gene mutations and chromosomal aberrations by reducing the efficiency of DNA repair. Defects in checkpoint control have been seen in certain hereditary cancer syndromes and at early stages of cell transformation. Mutations in checkpoint control genes therefore may contribute to the genetic instability that appears to drive neoplastic evolution.

 The activity of the Cyclin B-cdc2 (CDK1) complex is pivotal in regulating the G2-phase transition wherein cdc2 is maintained in an inactive state by the tyrosine kinases Wee1 and Myt1. It is thought that coordinated action of the kinase Aurora A and the cofactor Bora activate PLK1 as cells approach the M-phase, which in turn activates the phosphatase cdc25 and downstream cdc2 activity, hence establishing a feedback amplification loop that efficiently drives the cell into mitosis. Importantly, DNA damage cues activate the sensory DNA-PK/ATM/ ATR kinases, which relay two parallel cascades that ultimately serve to inactivate the Cyclin B-cdc2 complex. In addition, sporadic and familial mutations in the DNA-repair proteins such as the BRCA-family, ATM, and the Fanconi Anemia proteins further highlight this as a key tumor suppressor checkpoint.

 Recently, many compounds in clinical status are designed for cell cycle arrest and modification on DNA replication for cancer therapy.

Targets List in Cell Cycle/DNA Damage