Abstract

Topoisomerase 2a (Topo2a)-dependent G 2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCe-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G 2 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 G 2 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 G 2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCe-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G 2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCe knockout mice, p53 deletion elicited tumors were less aggressive than in PKCe-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 PKCe-directed therapeutic intervention. Significance: The identification of a requirement for p53 in stringent Topo2a-dependent G 2 arrest and engagement of PKCe failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality.

Original languageEnglish
Pages (from-to)1762-1773
Number of pages12
JournalCancer Research
Volume82
Issue number9
Early online date1 Mar 2022
DOIs
Publication statusPublished - 3 May 2022

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