Robust DNA Damage Response and Elevated Reactive Oxygen Species in TINF2-Mutated Dyskeratosis Congenita Cells.

摘要: Dyskeratosis Congenita (DC) is an inherited multisystem premature aging disorder with characteristic skin and mucosal findings as well a predisposition to cancer bone marrow failure. DC arises due gene mutations associated the telomerase complex or telomere maintenance, resulting in critically shortened telomeres. The pathogenesis of DC, several congenital failure (BMF) syndromes, converges on DNA damage response (DDR) pathway subsequent elevation reactive oxygen species (ROS). Historically, patients have had poor outcomes following transplantation (BMT), perhaps consequence underlying hypersensitivity cytotoxic agents. Previously, we demonstrated activated DDR increased ROS, augmented by chemotherapy radiation, somatic cells isolated from mutation RNA component telomerase, TERC. current study was undertaken determine whether previous related ROS TERC patients’ could be extended other mutations. Of particular interest antioxidant approach counter decrease pathologies. To test this, examined lymphocytes different (TERT, TINF2, TERC) for presence active ROS. All led steady-state p53 (2-fold 10-fold) (1.5-fold 2-fold). Upon exposure ionizing radiation (XRT), both significant degree. Exposing hydrogen peroxide also revealed that maintain oxidant burden compared controls 3-fold). cell culture supplemented N-acetylcysteine, alternatively grown low oxygen, afforded proliferative benefits (proliferation: maximum 2-fold increase; NAC: 5-fold decrease; oxygen: 3.5-fold decrease). Together, our data supports mechanism whereby deficiency telomeres initiate create pro-oxidant environment, especially carrying TINF2 Finally, ameliorative effects antioxidants vitro suggest this translate therapeutic patients.