Redox regulation of SUMO enzymes is required for ATM activity and survival in oxidative stress

Abstract

To sense and defend against oxidative stress, cells depend on signal transduction cascades involving redox-sensitive proteins. We previously identified SUMO (small ubiquitin-related modifier) enzymes as downstream effectors of reactive oxygen species (ROS). Hydrogen peroxide transiently inactivates SUMO E1 and E2 enzymes by inducing a disulfide bond between their catalytic cysteines. How important their oxidation is in light of many other redox-regulated proteins has however been unclear. To selectively disrupt this redox switch, we identified a catalytically fully active SUMO E2 enzyme variant (Ubc9 D100A) with strongly reduced propensity to maintain a disulfide with the E1 enzyme in vitro and in cells. Replacement of Ubc9 by this variant impairs cell survival both under acute and mild chronic oxidative stresses. Intriguingly, Ubc9 D100A cells fail to maintain activity of the ATM-Chk2 DNA damage response pathway that is induced by hydrogen peroxide. In line with this, these cells are also more sensitive to the ROSproducing chemotherapeutic drugs etoposide/Vp16 and Ara-C. These findings reveal that SUMO E1~E2 oxidation is an essential redox switch in oxidative stress.

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

“…For example, sumoylation of ATR and its cofactor ATRIP in human cells supports genotoxin survival by boosting ATRIP interactions with other checkpoint factors and thus enhancing the checkpoint response (Wu et al, 2014; Wu and Zou, 2016). In contrast, ATM-mediated DNA damage checkpoint and cellular survival are promoted by transient inactivation of SUMO E1 and E2 via oxidative stress-induced disulfide bond formation between their catalytic cysteines (Stankovic-Valentin et al, 2016). These rather complex interactions between sumoylation and DNA damage checkpoint proteins under various conditions require further investigation to deconvolute the specific outcomes linked to distinct molecular mechanisms.…”

Free d-aspartate triggers NMDA receptor-dependent cell death in primary cortical neurons and perturbs JNK activation, Tau phosphorylation, and protein SUMOylation in the cerebral cortex of mice lacking d-aspartate oxidase activity

“…Next, we investigated protein SUMOylation levels, known to be associated with oxidative stress in cell cultures (Feligioni et al, 2011;Stankovic-Valentin et al, 2016) and in animal models of AD (Marcelli et al, 2017) and connected with JNK activation (Feligioni et al, 2011). Interestingly, Western blot experiments revealed an overall increase in SUMO1 protein levels in the PFC of Ddo −/− mice at all ages analyzed compared to Ddo +/+ littermates (two-way ANOVA, age × genotype interaction, F (2,12) = 9.22, p = .004; Fig.…”

The crosstalk between trace elements with DNA damage response, repair, and oxidative stress in cancer

“…106,107 Finally, small ubiquitin related modifier (SUMO) enzymes are downstream mediators of ROS, and essential for ATM activity and survival under OS. 108 ROS can promote expression of cyclin D1, phosphorylation of extracellular signal-regulated kinase (ERK), JUN N-terminal kinase (JNK), and activation of mitogenactivated protein kinase (MAPK), all of which are connected to cancer progression. In addition, ROS have been found to decrease expression of tumor suppressors, including protein tyrosine phosphatases (PTPs) and phosphatase and tensin homolog (PTEN).…”