Figure 6: TREX1-deficient cells are DNA repair-proficient, but more sensitive to type I interferon-dependent stimuli.

(a,b) Knockdown of TREX1 (siTREX1) in HeLa cells causes phosphorylation of p53 and IRF3 along with induction of IFN-β. This is abrogated in cells with additional knockdown of STING (siTREX+siSTING). siCtrl, negative control siRNA. ***P<0.001 versus siCtrl; ^###P<0.001 versus siTREX1. (c) Constitutive activation of IFN-β in TREX1-deficient fibroblasts (SLE, AGS) is further enhanced by siRNA-induced knockdown of RPA70 (siRPA) or Rad51 (siRad51) or both (siRPA+siRad51). This is suppressed by additional knockdown of cGAS (sicGAS). Shown are the means of one experiment run in triplicates out of two independent experiments. Error bars, s.d. *P<0.001 versus siCtrl. ^#P<0.001 versus knockdown of RPA70, Rad51 or RPA70 and Rad51, respectively, by analysis of variance followed by Tukey’s post hoc test. (d) Repair kinetics of CPDs (left) and DSBs (right) in response to solar-simulated radiation (SSR). Means and s.e.m. of at least three independent experiments for each patient and wild-type control cell lines (WT, n=5). *P<0.05 (LE1, LE2) and **P<0.01 (AGS1, AGS2) immediately after ultraviolet exposure for CPDs, *P<0.05 (LE1, LE2) and **P<0.01 (AGS1, AGS2) at 6 h for DSBs. Although TREX1-deficient cells react more sensitive to SSR than WT cells, both DNA lesions are efficiently repaired within 24 h post irradiation. (e) IFNB upregulation in patient fibroblasts challenged with poly(I:C) and ultraviolet C irradiation. (WT, n=2). Means and s.e.m. of five independent experiments. *P<0.05; **P<0.01; ***P<0.001 versus WT. *P<0.05 (AGS2); **P<0.01 (LE1); ***P<0.001 (LE2, AGS1) for poly(I:C) versus poly(I:C) plus ultraviolet C. Mann–Whitney U-test.