DNA-damage response network at the crossroads of cell-cycle checkpoints,cellular senescence and apoptosis |
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| Authors: | Schmitt Estelle Paquet Claudie Beauchemin Myriam Bertrand Richard |
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| Institution: | (1) Notre Dame Hospital and Montreal Cancer Institute, Research Centre of University of Montreal Hospital Centre (CRCHUM), Montreal, Que, H2L 4M1, Canada;(2) Medicine Department, University of Montreal, Montreal, Que, H3C 3J7, Canada |
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| Abstract: | Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death.
Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence
is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells
by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle,
cellular senescence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently
apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed
how the DNA damage-sensing and-signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation,
cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving “sensor” proteins that sense
the damage, and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins
implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and
apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions
in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now
revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence,
effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding
the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss
the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.
Project supported by the Canadian Institutes of Health Research and the Cancer Research Society, and fellowships by the Health
Research Funds of Quebec, Canada |
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| Keywords: | DNA-damage response network Cell cycle Cellular senescence Apoptosis Bcl-2 family |
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