DNA polymerase η promotes nonhomologous end joining upon etoposide exposure dependent on the scaffolding protein Kap1.

DNA polymerase eta (Pol η) is a eukaryotic member of the Y-family of DNA polymerase involved in translesion DNA synthesis and genome mutagenesis. Recently, several translesion DNA synthesis polymerases have been found to function in repair of DNA double-strand breaks (DSBs). However, the role of Pol η in promoting DSB repair remains to be well defined. Here, we demonstrated that Pol η could be targeted to etoposide (ETO)-induced DSBs and that depletion of Pol η in cells causes increased sensitivity to ETO. Intriguingly, depletion of Pol η also led to a nonhomologous end joining repair defect in a catalytic activity-independent manner. We further identified the scaffold protein Kap1 as a novel interacting partner of Pol η, the depletion of which resulted in impaired formation of Pol η and Rad18 foci after ETO treatment. Additionally, overexpression of Kap1 failed to restore Pol η focus formation in Rad18-deficient cells after ETO treatment. Interestingly, we also found that Kap1 bound to Rad18 in a Pol η-dependent manner, and moreover, depletion of Kap1 led to a significant reduction in Rad18-Pol η association, indicating that Kap1 forms a ternary complex with Rad18 and Pol η to stabilize Rad18-Pol η association. Our findings demonstrate that Kap1 could regulate the role of Pol η in ETO-induced DSB repair via facilitating Rad18 recruitment and stabilizing Rad18-Pol η association.

[Matrix stiffening related lncRNA SNHG8 regulates chemosensitivity of ovarian cancer].

Extracellular matrix (ECM) has been implicated in tumor progress and chemosensitivity. Ovarian cancer brings a great threat to the health of women with a significant feature of high mortality and poor prognosis. However, the potential significance of matrix stiffness in the pattern of long non-coding RNAs (lncRNAs) expression and ovarian cancer drug sensitivity is still largely unkown. Here, based on RNA-seq data of ovarian cancer cell cultured on substrates with different stiffness, we found that a great amount of lncRNAs were upregulated in stiff group, whereas SNHG8 was significantly downregulated, which was further verified in ovarian cancer cells cultured on polydimethylsiloxane (PDMS) hydrogel. Knockdown of SNHG8 led to an impaired efficiency of homologous repair, and decreased cellular sensitivity to both etoposide and cisplatin. Meanwhile, the results of the GEPIA analysis indicated that the expression of SNHG8 was significantly decreased in ovarian cancer tissues, which was negatively correlated with the overall survival of patients with ovarian cancer. In conclusion, matrix stiffening related lncRNA SNHG8 is closely related to chemosensitivity and prognosis of ovarian cancer, which might be a novel molecular marker for chemotherapy drug instruction and prognosis prediction.

Prognostic pyroptosis-related lncRNA signature predicts the efficacy of immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a common malignant tumor of the liver, remains high incidence and poor prognosis. Although pyroptosis as well as lncRNA have been believed to play important roles in the tumorigenesis, diagnosis and prognosis, the role of pyroptosis-related lncRNAs (PRlncRs) in HCC remains obscure. Here, we identified 73 significantly differentially expressed and overall survival (OS) related pyroptosis-related lncRNAs (PRlncRs) in noncancerous and HCC samples. Based on LASSO regression and Cox regression analyses, we set up a novel prognostic model including six PRlncRs (MKLN1-AS, AC139491.2, AC145207.5, AC099850.3, AL590705.3 and AL049840.5), which showed good correlation with the OS of HCC patients. Considering that the risk score was negatively related to clinicopathologic features including T stage (T1-2 and T3-4), clinical stage (stage I-II and stage III-IV) and histological grade (G1, G2, G3 and G4), we further constructed a predictive nomogram containing the risk score and other clinicopathological features to predict the OS rates for HCC patients. In addition, the proposed signature was closely related to immune infiltration and offered improved clinical utility for immune checkpoint inhibitors (ICIs) strategies and chemotherapeutic drug selection in HCC. In conclusion, we established a considerable accurate risk signature consisting of 6 PRlncRs in HCC, which could predict the prognosis and efficacy of immunotherapy for HCC patients.