Biology subjects

Guerrero, E. N.

Publications and source records attributed to Guerrero, E. N..

3 recordsLinked to original sources

bioRxiv2026

Refined USP25/28 inhibitors with improved selectivity towards c-Myc driven squamous lung cancer cells

The ubiquitin specific protease 28 (USP28) is implicated in tumorigenesis by controlling the turnover of substrates including the oncogene c-MYC and the ubiquitin ligase FBW7. Here, we describe small molecule inhibitors of USP25 and USP28, leading to cancer cell cycle arrest and death. However, genetic deletion of USP25/28 does not replicate this effect. An integrated -omics approach revealed off-target effects for thienopyridine and thienopyrazine carboxamide compounds in protein translation. Chemoproteomics and biochemical analyses suggested binding of such compounds to a region near the ribosome complex polypeptide exit tunnel. Structural analysis of a USP28-inhibitor complex enabled the design of modified USP25/28 inhibitor molecules which minimized translation-related off-target effects. In distinction to earlier compounds, the optimized inhibitors were non-toxic to breast cancer cells yet retained potent anti-proliferative activity in squamous lung carcinoma cells, where USP28 is associated with disease progression. Together, our results demonstrate that refined USP25/28 inhibitors can selectively suppress tumor growth by targeting c-MYC driven pathways, offering a more precise therapeutic strategy for treating squamous lung cancers whilst minimizing undesired cytotoxicity.

cancer biology↗

bioRxiv2022

IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in ALS6 MNs. Furthermore, ALS6 MNs are more sensitive to oxidative stress and display reduced expression of TGF-{beta} and mTORC gene pathways when stressed. Finally, we show that IFN{gamma} treatment reduces apoptosis of ALS6 MNs exposed to oxidative stress and partially restores the translation rates in ALS6 MNs. Overall, these findings suggest that a functional IFN{gamma} response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6. Highlights and eTOC blurbO_LIALS6 patient-derived motor neurons show decreased viability and reduced production of innate immune cytokines following oxidative stress C_LIO_LIFUS cytoplasmic localization coincides with decreased protein synthesis rates C_LIO_LIIFN{gamma} treatment of ALS6 patient-derived motor neurons reduces apoptosis and ameliorates translation rates resulting from oxidative stress C_LI

neuroscience↗

bioRxiv2022

Regulated Degradation of the Inner Nuclear Membrane Protein SUN2 Maintains Nuclear Envelope Architecture and Function

Nuclear architecture and functions depend on dynamic interactions between nuclear components (such as chromatin) and inner nuclear membrane (INM) proteins. Mutations in INM proteins interfering with these interactions result in disease. However, mechanisms controlling the levels and turnover of INM proteins remain unknown. Here, we describe a mechanism of regulated degradation of the INM SUN domain-containing protein 2 (SUN2). We show that Casein Kinase II and the C-terminal domain Nuclear Envelope Phosphatase 1 (CTDNEP1) have opposing effects on SUN2 levels by regulating SUN2 binding to the ubiquitin ligase Skp/Cullin1/F-Box{beta}TrCP (SCF{beta}TrCP). Upon binding to phosphorylated SUN2, SCF{beta}TrCP promotes its ubiquitination. Ubiquitinated SUN2 is membrane extracted by the AAA ATPase p97 and delivered to the proteasome for degradation. Importantly, accumulation of non-degradable SUN2 results in aberrant nuclear architecture, vulnerability to DNA damage and increased lagging chromosomes in mitosis. These findings uncover a central role of proteolysis in INM protein homeostasis.

cell biology↗