DNA double‐strand break response in stem cells: Mechanisms to maintain genomic integrity

• Published in: Biochimica et biophysica acta 2013-02, Vol.1830 (2), p.2345-2353
• Main Authors: Nagaria, Pratik, Robert, Carine, Rassool, Feyruz V.
• Format: Article
• Language: English
• Subjects: DNA; DNA Damage; DNA Repair; Double‐strand break repair; Embryonic stem cell; embryonic stem cells; Embryonic Stem Cells - metabolism; genome; Genomics; genotoxicity; Humans; Induced pluripotent stem cell; induced pluripotent stem cells; ionizing radiation; oxidative stress; reactive oxygen species; Reactive Oxygen Species - metabolism; somatic cells
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.09.001

Embryonic stem cells (ESCs) represent the point of origin of all cells in a given organism and must protect their genomes from both endogenous and exogenous genotoxic stress. DNA double-strand breaks (DSBs) are one of the most lethal forms of damage, and failure to adequately repair DSBs would not only compromise the ability of SCs to self-renew and differentiate, but will also lead to genomic instability and disease. Herein, we describe the mechanisms by which ESCs respond to DSB-inducing agents such as reactive oxygen species (ROS) and ionizing radiation, compared to somatic cells. We will also discuss whether the DSB response is fully reprogrammed in induced pluripotent stem cells (iPSCs) and the role of the DNA damage response (DDR) in the reprogramming of these cells. ESCs have distinct mechanisms to protect themselves against DSBs and oxidative stress compared to somatic cells. The response to damage and stress is crucial for the maintenance of self-renewal and differentiation capacity in SCs. iPSCs appear to reprogram some of the responses to genotoxic stress. However, it remains to be determined if iPSCs also retain some DDR characteristics of the somatic cells of origin. The mechanisms regulating the genomic integrity in ESCs and iPSCs are critical for its safe use in regenerative medicine and may shed light on the pathways and factors that maintain genomic stability, preventing diseases such as cancer. This article is part of a Special Issue entitled Biochemistry of Stem Cells. ► Components of the DNA damage response (DDR) are critical in maintaining genomic integrity of ESCs and iPSCs. ► Failure to adequately repair DSBs can lead to genomic instability and cancer ► ESCs have unique mechanisms for maintaining a highly error-free form of DSB repair. ► DSB response may not be completely reprogrammed in all iPSCs. ► DDR presents a roadblock to high efficacy of iPSC generation during reprogramming.