DNA Damage Stress: Cui Prodest?

Abstract

DNA is an entity shielded by mechanisms that maintain genomic stability and are essential for living cells; however, DNA is constantly subject to assaults from the environment throughout the cellular life span, making the genome susceptible to mutation and irreparable damage. Cells are prepared to mend such events through cell death as an extrema ratio to solve those threats from a multicellular perspective. However, in cells under various stress conditions, checkpoint mechanisms are activated to allow cells to have enough time to repair the damaged DNA. In yeast, entry into the cell cycle when damage is not completely repaired represents an adaptive mechanism to cope with stressful conditions. In multicellular organisms, entry into cell cycle with damaged DNA is strictly forbidden. However, in cancer development, individual cells undergo checkpoint adaptation, in which most cells die, but some survive acquiring advantageous mutations and selfishly evolve a conflictual behavior. In this review, we focus on how, in cancer development, cells rely on checkpoint adaptation to escape DNA stress and ultimately to cell death.

Keywords: G2-arrest; adaptation; cell cycle checkpoints; cell death; genomic instability; repair of DNA damage.

Figure 1

Cell fates following DNA Damage. Cell cycle checkpoint is induced by DNA damage. Cell cycle entry occurs after the DNA damages have been fully repaired, or alternatively, cells have two possible fates, to die or survive after a process of adaptation that allows cell division with unrepaired DNA lesions.

Figure 2

Schematic representation of the sensors, transducers and mediators involved in DNA damage response (DDR) pathways. DNA damage response is sensed and repaired by multi-protein complexes. Depending on the level of injury, the signaling triggered by the damage response will result in different cellular fates.