SENP3-mediated De-conjugation of SUMO2/3 from Promyelocytic Leukemia Is Correlated with Accelerated Cell Proliferation under Mild Oxidative Stress

Abstract

Small ubiquitin-like modifier (SUMO) 2/3 is known to conjugate to substrates in response to a variety of cellular stresses. However, whether and how SUMO2/3-specific proteases are involved in de-conjugation under cell stress is unclear. Here, we show that low doses of hydrogen peroxide (H 2 O 2 ) induce an increase of the SENP3 protein, which removes SUMO2/3 from promyelocytic leukemia (PML). Low dose H 2 O 2 causes SENP3 to co-localize with PML bodies and reduces the number of PML bodies in a SENP3-dependent manner. Furthermore, de-conjugation of SUMO2/3 from PML is responsible for the accelerated cell proliferation caused by low dose H 2 O 2 . Knocking down PML promotes basal cell proliferation as expected. This can be reversed by reconstitution with wild-type PML but not its mutant lacking SUMOylation, indicating that only the SUMOylated PML can play an inhibitory role for cell proliferation. Thus, SENP3 appears to be a key mediator in mild oxidative stress-induced cell proliferation via regulation of the SUMOylation status of PML. Furthermore, SENP3 is over-accumulated in a variety of primary human cancers including colon adenocarcinoma in which PML is hypo-SUMOylated. These results reveal an important role of SENP3 and the SUMOylation status of PML in the regulation of cell proliferation under oxidative stress.

The biphasic redox sensing of SENP3 accounts for the HIF-1 transcriptional activity shift by oxidative stress

“…The ROS level regulates the SENP3-p300 interaction by affecting different cysteines Our previous studies [26,27] have shown that the decrease in the SUMO2/3 modification of p300 during mild stress is due to an accumulation of SENP3. We also found that this accumulation following a blockage of ubiquitination can be attributed to the oxidation of cysteines 243 or 274 within the redox sensing domain of SENP3; the mutants (C243S or C274S) in which these cysteines were replaced by serine, an amino acid residue non-responsive to ROS, failed to accumulate under stress [35] .…”

“…The SENP3-mediated deconjugation of SUMO2/3 from p300, the co-activator for HIF-1, is beneficial for HIF-1 transcriptional activity under both hypoxic and normoxic conditions. Being different with the other SENPs family members, SENP3 is specifically and sensitively responsive to low oxidative stress [26,27] . SENP3 is stabilized upon exposure to hydrogen peroxide (H 2 O 2 ) at very low doses, for instance, 0.05 mmol/L, and redistributes from the nucleolus to the nucleoplasm, which allows it to modulate various nuclear events, including the enhancement of HIF-1 transactivation.…”

Covalent Small Ubiquitin-like Modifier (SUMO) Modification of Maf1 Protein Controls RNA Polymerase III-dependent Transcription Repression

“…Thus, it is likely that the specificity of the SUMOylation events that drive tumor development is dictated by the expression and activity of the SUMO E3 ligases and the SENP proteases. Several SENPs, including SENP1 and SENP3, are overexpressed in the early stages of various carcinomas (25,26), indicating that select deSUMOylation events mediated by specific SENP proteins drives cancer development. Consistent with this idea, we find that SENP1 controls Maf1 SUMOylation.…”

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

“…prostate Overexpression of SENP1 [131,132] Overexpression of SENP3 [101] colon Overexpression of SENP1 [133] Overexpression of SENP3 [134] liver Downregulation of SENP2 [135] Overexpression of SENP6 [136] bladder Downregulation of SENP2 [137] gastric Overexpression of SENP3 [138] Trends Biochem Sci. Author manuscript; available in PMC 2016 June 01.…”