Dansen, T. B. | bioRxiv Science

bioRxiv2020

A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

DNA replication is challenged by numerous exogenous and endogenous factors that can interfere with the progression of replication forks. Stalling or slowing of the replication fork as a result of replication stress leads to formation of aberrant single-stranded DNA (ssDNA) stretches and potentially DNA double-stranded-breaks (DSBs). Accumulation of ssDNA activates the ATR-dependent DNA replication stress checkpoint response that slows progression from S/G2- to M-phase to protect genomic integrity (1). However, whether mild replication stress restricts proliferation remains controversial (2-6). Here we identify a novel cell cycle exit mechanism, that prevents S/G2 phase arrested cells from undergoing mitosis after exposure to mild replication stress through premature activation of the CDH1 bound Anaphase Promoting Complex / Cyclosome (APC/CCDH1). We find that replication stress causes a gradual decrease of the levels of the APC/CCDH1 inhibitor EMI1/FBXO5 through Forkhead Box O (FOXOs) mediated repression of its transcriptional regulator E2F1. By doing so, FOXOs limit the time during which the replication stress checkpoint is reversible, and thereby play an important role in maintaining genomic stability.

molecular biology↗

bioRxiv2019

Redox signaling modulates Rho activity and tissue contractility in the C. elegans spermatheca

Actomyosin based contractility in smooth muscle and non-muscle cells is regulated by signaling through the small GTPase Rho and by calcium-activated pathways. We use the myoepithelial cells of the Caenorhabditis elegans spermatheca to study the mechanisms of coordinated myosin activation in vivo. Here, we demonstrate that redox signaling regulates RHO-1/Rho activity in this contractile tissue. Exogenous hydrogen peroxide treatment decreases spermathecal contractility by inhibiting RHO-1, which is mediated through a conserved cysteine in its active site (C20). Further, we identify a gradient of oxidation across the spermathecal tissue, which is regulated by the cytosolic superoxide dismutase, SOD-1. SOD-1 functions in the Rho pathway to inhibit RHO-1 through oxidation of C20. Our results suggest that SOD-1 functions to regulate the redox environment and to fine-tune Rho activity across the spermatheca.

cell biology↗