Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein

Abstract

Conflict of interest: JT is a cofounder of Principia Biopharma, which has licensed the p90RSK inhibitor FMK-MEA.

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

“…The role of ANAPC4 in cancer has not been studied in detail. RPS6KA1 interacts with TERF2IP to mediate telomere shortening and WFS1 had been found in close proximity to TERF1 in a fluorescence localisation screen [ 90 , 230 ]. ANAPC4 is predicted to influence telomere maintenance due to a yeast homologue having a role in telomere biology [ 231 ].…”

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

“…Additionally, highly reactive hydroxyl radicals, which are formed via the previously discussed reaction between H 2 O 2 and iron, cause telomeric DNA strand breaks by reacting with deoxyribose hydrogen atoms, which further exacerbates senescence and SASP ( Mello Filho et al, 1984 ; Balasubramanian et al, 1998 ; Li et al, 2013 ; Coluzzi et al, 2019 ). mtROS-mediated activation of p90RSK also promotes senescence by phosphorylating telomeric repeat-binding factor 2–interacting protein (TERF2IP) and exporting the TERF2IP-TRF2 from the nucleus to the cytosol ( Rovillain et al, 2011 ; Kotla et al, 2019 ). This cytosolic TERF2IP, which is phosphorylated at serine 205 by p90RSK, is responsible for activating NF-kB, a known contributor to premature aging and inflammation ( Tilstra et al, 2011 ; Kotla et al, 2019 ).…”

“…mtROS-mediated activation of p90RSK also promotes senescence by phosphorylating telomeric repeat-binding factor 2–interacting protein (TERF2IP) and exporting the TERF2IP-TRF2 from the nucleus to the cytosol ( Rovillain et al, 2011 ; Kotla et al, 2019 ). This cytosolic TERF2IP, which is phosphorylated at serine 205 by p90RSK, is responsible for activating NF-kB, a known contributor to premature aging and inflammation ( Tilstra et al, 2011 ; Kotla et al, 2019 ). TERF2IP and TRF2 are also components of the Shelterin complex, which is responsible for preserving the structure of telomeres, so their depletion from the nucleus leads to telomere shortening and cellular senescence ( Dominic et al, 2020a ).…”

Time-dependent replicative senescence vs. disturbed flow-induced pre-mature aging in atherosclerosis

“…In addition, mutant mice developed age dependent vascular dysfunction. [ 55 ] Spindle assembly checkpoint protein BubR1 Detect the correct microtubule-kinetochore attachment and segregation of chromatids during mitosis Hypomorphic BubR1 mutant (BubR1 H/H ) Mice expressing mutant BubR1 Increased production of superoxide anions, aging-associated phenotypes, EC dependent relaxation is lost, accelerated cardio vascular aging [ 56 , 57 ] Telomerase and Shelterin complex TERC, TERT TERT produces telomeric repeats using the template provided by TERC TERC −/− and TERT −/− mice Telomerase deficient mice exhibited an increased activity of nicotinamide adenine dinucleotide phosphate oxidase, and high levels of reactive oxygen species, leading to increased hypertension and vascular dysfunction [ 58 ] TERF2IP A member of the shelterin complex of the mammalian TLs binds to both telomeric and nontelomeric chromatins and in the protection of TLs TERF2IP −/− mice Conferred protection against d-flow–induced EC senescence, apoptosis, and AS plaque formation [ 59 ] Base Excision Repair of Oxidative DNA Damage Base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) Involved in the BER mechanism for the repairing of 8-Oxoguanine (8oxoG), which is one of the most abundant oxidative DNA damage OGG1 −/− mice in vascular smooth muscle cells (VSMC) Mice exhibited oxidative stress, DNA strand breaks, pro-inflammatory pathways and extensive AS formation [ 60 ] Apurinic/Apyrmidinic Endonuclease-1 (APE1)/redox factor-1 (ref-1) Essential for BER pathway, DNA repair and governs the reductive activation of many redox-sensitive transcription factors APE1/ref-1 +/− mice The transgenic mice manifested reduced vascular NO level, dysregulated EC dependent vascular tone and developed systemic hyper tension and vascular complications [ 61 ] …”

“…Recently our group reported the dual role of TERF2IP in ECs depending on whether it is in the nucleus and the cytosol [ 59 ]. Under normal conditions, the TERF2IP-TRF2 complex is in the shelterin complex associated with telomers conferring a protective role, preventing telomeres from shortening ( Fig.…”