Regulation of the Cell Cycle, Cell Cycle Checkpoints, and Cancer

Abstract

DNA damage response (DDR) pathways are triggered to ensure proper repair of DNA lesions and preserve genome integrity. Key intracellular transducers of the DNA damage are ataxia‐telangiectasia mutated kinase (ATM) and ataxia‐telangiectasia and Rad3‐related kinase (ATR). These nuclear proteins, through dynamic interaction with chromatin‐bound sensory components and phosphorylation at T/SQ residues of a multitude of substrates, including the checkpoint kinases Chk1 and Chk2, activate a network of pathways important for DNA repair, multiple cell cycle–phase arrest, transcription, and apoptosis. Interestingly, the DDR machinery is a key mediator of telomere‐dependent and telomere‐independent forms of cellular senescence, and provides a barrier to aberrant DNA replication induced by oncogenic stimuli. These findings and the constitutive activation of the DDR in human precancerous lesions, underscore the role of the DDR as a tumour suppressor constraining transformation by driving incipient tumour cells into apoptosis or senescence. Since genetic abnormalities of the DDR hypersensitize to genotoxic anticancer agents, this pathway represents a relevant target to increase tumour cell kill and possibly overcome drug resistance. The promising results with a number of chemical inhibitors of ATM, Chk1 and Chk2 are paving the way for new chemoradiation strategies that exploit the DDR machinery.

Two new CHEK2 germ-line variants detected in breast cancer/sarcoma families negative for BRCA1, BRCA2, and TP53 gene mutations

“…The checkpoint kinase Chk2, encoded by the CHEK2 gene (MIM#604373) has been implicated in DNA repair, cell cycle arrest, and apoptosis in response to DNA double-strand breaks [1][2][3]. Following DNA damage, ATM phosphorylates Chk2 on Thr68, triggering its activation [4], and allowing it to phosphorylate a spectrum of biologically relevant substrates, including Cdc25C, p53, and BRCA1.…”

“…Defects in the DNA damage response pathways contribute to genetic instability and eventually cancer as a result of accumulation of mutations [1]. The checkpoint kinase Chk2, encoded by the CHEK2 gene (MIM#604373) has been implicated in DNA repair, cell cycle arrest, and apoptosis in response to DNA double-strand breaks [1][2][3].…”