The response to DNA damage during differentiation: Pathways and consequences

• Stem cells address DNA damage differently from their somatic counterpart.
• Embryo stem cells present efficient DNA repair/DNA damage response systems.
• Adult stem cells are at risk for mutation accumulation because of the use of NHEJ.
• Post-mitotic cells present restricted DNA repair/DNA damage response.
• Autophagy plays an important role during differentiation and in stem cell maintenance.

Damage to genomic DNA triggers a prompt set of signaling events known as the DNA damage response (DDR) which coordinates DNA repair, cell cycle arrest and ultimately cell death or senescence. Although activation of adequate DNA damage signaling and repair systems depends on the type of lesion and the cell-cycle phase in which it occurs, emerging evidence indicates that DNA repair and DDR function differently in different cellular contexts. Depending on the time maintenance and function of a specific cell type the risk of accumulating DNA damage may vary. For instance, damage to stem cells if not repaired can lead to mutation amplification or propagation through the processes of self-renewal and differentiation, respectively, whereas damage to post-mitotic cells can affect mostly tissue homeostasis. Stem cells are therefore expected to address DNA damage differently from their somatic counterparts. In this review the information available on the common and distinct mechanisms of control of genome integrity utilized by different cell types along the self-renewal/differentiation program will be reviewed, with special emphasis on their roles in the prevention of aging and disease.