Tpz1TPP1 SUMOylation reveals evolutionary conservation of SUMO-dependent Stn1 telomere association

Elongation of the telomeric overhang by telomerase is counteracted by synthesis of the complementary strand by the CST complex, CTC1(Cdc13)/Stn1/Ten1. Interaction of budding yeast Stn1 with overhang-binding Cdc13 is increased by Cdc13 SUMOylation. Human and fission yeast CST instead interact with overhang-binding TPP1/POT1. We show that the fission yeast TPP1 ortholog, Tpz1, is SUMOylated. Tpz1 SUMOylation restricts telomere elongation and promotes Stn1/Ten1 telomere association,and a SUMO-Tpz1 fusion protein has increased affinity for Stn1. Our data suggest that SUMO inhibits telomerase through stimulation of Stn1/Ten1 action by Tpz1, highlighting the evolutionary conservation of the regulation of CST function by SUMOylation

Inhibition of poly (ADP-Ribose) polymerase-1 in telomerase deficient mouse embryonic fibroblasts increases arsenite-induced genome instability

10.1186/2041-9414-1-5Genome Integrity1

Additional file 1 of Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes

Supplementary Material 1: Supplementary Figures and Table

Association of leukocyte telomere length with obesity-related traits in Asian children with early-onset obesity

10.1111/ijpo.12771PEDIATRIC OBESITY16

Urine leucine-rich alpha-2 glycoprotein 1 (LRG1) predicts the risk for progression to end stage kidney disease in patients with type 2 diabetes

   Objective: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is recently identified as an amplifier of transforming growth factor (TGF)- beta- induced kidney fibrosis in animal models. We aim to study whether urine LRG1 is associated with risk for progression to end stage kidney disease (ESKD) in individuals with type 2 diabetes.  Design and Methods: 1837 participants with type 2 diabetes and eGFR above 30 ml/min/1.73m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk for ESKD (progression to sustained eGFR Results: 134 incident ESKD events were identified during a median follow-up of 8.6 (IQR 5.8-9.6) years. As compared to the lowest tertile, participants with baseline urine LRG1 in the highest tertile had 1.91 (95% CI 1.04- 3.50) folds increased risk for progression to ESKD after adjustment for cardio-renal risk factors including eGFR and albuminuria. As a continuous variable, one SD increment in urine LRG1 was associated with 1.53 (95% CI 1.19-1.98) folds adjusted risk for ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD.  Conclusions: Urine LRG1, a TGF-beta signalling modulator, predicts risk for progression to ESKD independent of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involving in the pathophysiological pathway leading to kidney disease progression. </p

Plasma tryptophan- kynurenine pathway metabolites and risk for progression to end stage kidney disease in patients with type 2 diabetes

Objective: We sought to study the associations between plasma metabolites in tryptophan-kynurenine pathway and the risk of progression to end stage kidney disease (ESKD) in patients with type 2 diabetes. Design and Methods: Plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid and xanthurenic acid concentrations were measured in discovery (N=1915) and replication (N=346) cohorts. External validation was performed in Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (N=1312). The primary outcome was a composite of incident ESKD (progression to eGFR < 15 ml/min/1.73m2, sustained dialysis or renal death). The secondary outcome was annual eGFR decline. Results: In discovery cohort, tryptophan was inversely associated with risk for ESKD and kynurenine-to-tryptophan ratio (KTR) was positively associated with risk for ESKD after adjustment for clinical risk factors including baseline eGFR and albuminuria (adjusted HR [95% CI], 0.62 [0.51-0.75] and 1.48 [1.20-1.84], per one SD). High levels of kynurenic acid and xanthurenic acid were associated with low risks of ESKD (0.74 [0.60-0.91] and 0.74 [0.60-0.91]). Consistently, high levels of tryptophan, kynurenic acid and xanthurenic acid were independently associated with a slower eGFR decline whilst a high KTR was predictive of a faster eGFR decline. Similar outcomes were obtained in replication cohort. Furthermore, the inverse association between kynurenic acid and risk of ESKD was externally validated in CRIC participants with diabetes (adjusted HR 0.78 [0.65-0.93]). Conclusion: Accelerated catabolism of tryptophan in kynurenine pathway may be involved in progressive loss of kidney function. However, shunting the kynurenine pathway toward kynurenic acid branch may potentially slow renal progression.</p

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

10.1038/s42003-021-02056-7COMMUNICATIONS BIOLOGY4