Accession Number : AD1044785

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

Descriptive Note : Technical Report,01 Jun 2016,31 May 2017

Corporate Author : University of Alabama at Birmingham Birmingham United States

Personal Author(s) : Goldman, Frederick ; Westin,Erik

Full Text :

Report Date : 01 Jun 2017

Pagination or Media Count : 20

Abstract : 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.

Descriptors :   CONGENITAL ABNORMALITIES , stem cells , deoxyribonucleic acids , ribonucleic acids , proteins , fibroblasts , RNA SEQUENCE ANALYSIS , bone marrow , BIOLOGICAL AGING , BONE MARROW , cell line , genes , drugs , gene expression

Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology

Distribution Statement : APPROVED FOR PUBLIC RELEASE