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DNA Damage and Oxidative Stress in Dyskeratosis Congenita: Analysis of Pathways and Therapeutic Stategies Using CPISPR and iPSC Model Systems

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University of Alabama at Birmingham Birmingham United States

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Dyskeratosis congenita is a disorder that arises due to prematurely shortened telomeres and characterized by a classical clinical triad ofleukoplakia, skin dyspigmentation and nail dystrophy with concomitant marrow failure. DC symptomology, to a degree, corresponds tocritically shortened telomeres that limits cellular replicative potential and thus prematurely exhausts stem cell pools. Our previous findingssupport a hypothesis whereby shortened telomeres increase DNA damage responses within the cell leading to heightened reactive oxygenspecies ROS. Recent work supported under this research grant have uncovered a suppressed steady-state RNA expression and proteinlevels of the NRF2 and NRF3 pathways within DC skin fibroblasts. This suppression is also found in cells exposed to an environment withexperimentally-elevated oxidative stress. Furthermore, preliminary RNA-Seq experiments suggest that senescence associated secretorypathway SASP is altered in DC cells and suppressed upon mobilization of telomerase. Finally, decreased oxidative stress levels could befound in DC cells upon forced expression of an NRF2 heterodimerizing protein, MAFG, suggesting that suppression of this pathway yieldsto an unmitigated increase in ROS. Together, these findings provide support for a mechanism whereby shortened telomeres mobilize aDNA damage response that in turn suppresses antioxidant proteins leading to an increase in oxidative stress.

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Technical Report,01 Jun 2016,31 May 2017



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Approved For Public Release;

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