A distinctive requirement for p53 in the genome protective Topoisomerase 2a-dependent G2 arrest in hTERT positive cancer cells

Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention.SignificanceThe identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality

An International Study of Management Perceptions of the Working Capital Process

Working capital literature is rather limited and the process of managing short‐term resources is not understood well by he academicians. In contrast the corporate managers are continuously involved in the working capital decision-making process, but their perspective is limited to the practice of their firm. In order to fill this gap in the working capital literature, a study of management perceptions of the working capital process was undertaken. A survey was used to collect the information from the sample of marketing, production, and financial executives in large corporations in Belgium, France, India and United States. The study intercepts management ranking of working capital objectives and indicates the need to improve finacial planning models to include explicitly short–run objectives; further, predictability of cash inflows and outflows is examined and the potential factors affecting the predictability are evaluated. Finally, this study examines the management perceptions of long-range objectives in order to provide a proper perspective to the short-run financial planning.© 1979 JIBS. Journal of International Business Studies (1979) 10,28–38