Cyclin-dependent kinase inhibitors (CDKIs) and the DNA damage response: The link between signaling pathways and cancer

• Genome integrity depends on the coordinated functioning of a network of DNA damage response (DDR) systems. • DNA damage and variety of stresses can activate the cell-cycle checkpoint. • DNA damage induces transcription of p53 target genes, including members of the cyclin kinase-dependent inhibitors (CDKIs) family. • Defects in the DNA damage response pathways or DNA repair leading to increased genetic mutations, which often result in the development of cancer. At the cellular level, DNA repair mechanisms are crucial in maintaining both genomic integrity and stability. DNA damage appears to be a central culprit in tumor onset and progression. Cyclin-dependent kinases (CDKs) and their regulatory partners coordinate the cell cycle progression. Aberrant CDK activity has been linked to a variety of cancers through deregulation of cell-cycle control. Besides DNA damaging agents and chromosome instability (CIN), disruptions in the levels of cell cycle regulators including cyclin-dependent kinase inhibitors (CDKIs) would result in unscheduled proliferation and cell division. The INK4 and Cip/Kip (CDK interacting protein/kinase inhibitor protein) family of CDKI proteins are involved in cell cycle regulation, transcription regulation, apoptosis, and cell migration. A thorough understanding of how these CDKIs regulate the DNA damage response through multiple signaling pathways may provide an opportunity to design efficient treatment strategies to inhibit carcinogenesis.