The mechanisms by which the p53 response is triggered following exposure to DNA-damaging agents have not yet been clearly elucidated. We and others have previously suggested that blockage of RNA polymerase II may be the trigger for induction of the p53 response following exposure to ultraviolet light. Here we report on the correlation between inhibition of mRNA synthesis and the induction of p53, p21 WAF1 and apoptosis in diploid human ®broblasts treated with either UV light, cisplatin or the RNA synthesis inhibitors actinomycin D, DRB, H7 and a-amanitin. Exposure to ionizing radiation or the proteasome inhibitor LLnL, however, induced p53 and p21 WAF1 without aecting mRNA synthesis. Importantly, induction of p53 by the RNA synthesis or proteasome inhibitors did not correlate with the induction of DNA strand breaks. Furthermore, cisplatin-induced accumulation of active p53 in repair-de®cient XP-A cells occurred despite the lack of DNA strand break induction. Our results suggest that the induction of the p53 response by certain toxic agents is not triggered by DNA strand breaks but rather, may be linked to inhibition of mRNA synthesis either directly by the poisoning of RNA polymerase II or indirectly by the induction of elongation-blocking DNA lesions.

BackgroundOvarian cancer (OV) is the most lethal gynecological cancer in women. We aim to develop a generalized, individualized immune prognostic signature that can stratify and predict overall survival for ovarian cancer.MethodsThe gene expression profiles of ovarian cancer tumor tissue samples were collected from 17 public cohorts, including 2777 cases totally. Single sample gene set enrichment (ssGSEA) analysis was used for the immune genes from ImmPort database to develop an immune-based prognostic score for OV (IPSOV). The signature was trained and validated in six independent datasets (n = 519, 409, 606, 634, 415, 194).FindingsThe IPSOV significantly stratified patients into low- and high-immune risk groups in the training set and in the 5 validation sets (HR range: 1.71 [95%CI: 1.32–2.19; P = 4.04 × 10−5] to 2.86 [95%CI: 1.72–4.74; P = 4.89 × 10−5]). Further, we compared IPSOV with nine reported ovarian cancer prognostic signatures as well as the clinical characteristics including stage, grade and debulking status. The IPSOV achieved the highest mean C-index (0.625) compared with the other signatures (0.516 to 0.602) and clinical characteristics (0.555 to 0.583). Further, we integrated IPSOV with stage, grade and debulking, which showed improved prognostic accuracy than clinical characteristics only.InterpretationThe proposed clinical-immune signature is a promising biomarker for estimating overall survival in ovarian cancer. Prospective studies are needed to further validate its analytical accuracy and test the clinical utility.FundThis work was supported by National Key Program of China, and Natural Science Foundation of the Jiangsu Higher Education Institutions of China.

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We identify cell-cycle roles for 22 of 117 Drosophila PPs. Involvement of several PPs in G(2) suggests multiple points for its regulation. Major mitotic roles are played by PP1 with tyrosine PPs and Myotubularin-related PPs having significant roles in regulating chromosome behavior. Finally, depending upon its regulatory subunits, PP2A regulates spindle bipolarity, kinetochore function, and progression into anaphase. Discovery of several novel cell-cycle PPs identifies a need for further studies of protein dephosphorylation.