Usp1

Spermiogenesis defines the final phase of male germ cell differentiation. While multiple deubiquitinating enzymes have been linked to spermiogenesis, the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis. We selectively deleted Uaf1 in premeiotic germ cells using the Stra8-Cre knock-in mouse strain ( Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. Further, UAF1 interacts and colocalizes with USP1 in the testes...

HER2-positive breast cancer is one of the most prevalent forms of cancer among women worldwide. Generally, the molecular characteristics of this breast cancer include activation of human epidermal growth factor receptor-2 (HER2) and hormone receptor activation. HER2-positive is associated with a higher death rate, which led to the development of a monoclonal antibody called trastuzumab, specifically targeting HER2. The success rate of HER2-positive breast cancer treatment has been increased; however, drug resistance remains a challenge...

The porcine reproductive and respiratory syndrome virus (PRRSV) can lead to severe reproductive problems in sows, pneumonia in weaned piglets, and increased mortality, significantly negatively impacting the economy. Post-translational changes are essential for the host-dependent replication and long-term infection of PRRSV. Uncertainty surrounds the function of the ubiquitin network in PRRSV infection. Here, we screened 10 deubiquitinating enzyme inhibitors and found that the ubiquitin-specific proteinase 1 (USP1) inhibitor ML323 significantly inhibited PRRSV replication in vitro ...

Circular RNAs (circRNAs) play a crucial role in regulating various tumors. However, their biological functions and mechanisms in gastric cancer (GC) have not been well understood. Here, we discovered a stable cytoplasmic circRNA named circUSP1 (hsa_circ_000613) in GC. CircUSP1 upregulation in GC tissues was correlated with tumor size and differentiation. We observed that circUSP1 promoted GC growth and metastasis. Mechanistically, circUSP1 mainly interacted with the RRM1 domain of an RNA-binding protein (RBP) called HuR, stabilizing its protein level by inhibiting β-TrCP-mediated ubiquitination degradation...

The ubiquitin-specific protease (USP) family of deubiquitinases (DUBs) controls cellular ubiquitin-dependent signaling events. This generates therapeutic potential, with active-site inhibitors in preclinical and clinical studies. Understanding of the USP active site is primarily guided by USP7 data, where the catalytic triad consists of cysteine, histidine, and a third residue (third critical residue), which polarizes the histidine through a hydrogen bond. A conserved aspartate (fourth critical residue) is directly adjacent to this third critical residue...

Ewing sarcoma is a cancer of bone and soft tissue in children and young adults that is driven by the EWS-ETS fusion transcription factor, most commonly EWS-FLI1. We previously reported that Ewing sarcoma harbors two populations of cells, the CD133high population displaying higher growth rate and the CD133low population displaying chemotherapy resistance. We now find that the ubiquitin-specific protease 1 (USP1) is a transcriptional target of the EWS-FLI1 fusion oncoprotein, expressed at high and low levels in the CD133high and the CD133low populations, respectively, and determines chemo-sensitivity...

Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor suppressor genes. BRD4, an acetyl-lysine binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics...

Endophytes can assist crops in adapting to high temperatures and drought conditions, thereby reducing agricultural losses. However, the mechanism through which endophytes regulate crop resistance to high temperatures and drought stress remains unclear, and concerns regarding safety and stability exist with active endophytes. Thus, heat-treated endophytic bacteria LSE01 (HTB) were employed as a novel microbial fertilizer to investigate their effects on plant adaptation to high temperatures and drought conditions...

DNA replication stress-induced fork arrest represents a significant threat to genomic integrity. One major mechanism of replication restart involves repriming downstream of the arrested fork by PRIMPOL, leaving behind a single-stranded DNA (ssDNA) gap. Accumulation of nascent strand ssDNA gaps has emerged as a possible determinant of the cellular hypersensitivity to genotoxic agents in certain genetic backgrounds such as BRCA deficiency, but how gaps are converted into cytotoxic structures is still unclear...

The ORF6 proteins encoded by sarbecoviruses are essential for effective viral replication and infection and are important targets for developing effective intervention strategies. In this study, we confirmed that sarbecovirus ORF6 proteins are important antagonists of the host immune response and identified the regulatory mechanisms of ubiquitination and deubiquitination of most sarbecovirus ORF6 proteins. Moreover, we revealed that DUB USP1 prevents the proteasomal degradation of all ORF6 proteins, thereby promoting the virulence of SARS-CoV-2...

The above article, published online on 4 March 2020 on Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal's Editor-in-Chief, Masanori Hatakeyama, the Japanese Cancer Association and John Wiley & Sons Australia, Ltd following concerns raised by a third party about figures within the article. During the journal's investigation into the concerns raised, the authors were not able to provide comprehensive original data for the relevant figures. Accordingly, the editors consider that the results in the published article are unreliable and do not sufficiently support the conclusions...

BACKGROUND: Gastric cancer (GC) is the most commonly diagnosed digestive system malignancy with a dismal survival outcome. The prognostic value of ubiquitination-related genes (URGs) in GC has yet to be discovered. METHODS: Two GC cohort datasets were obtained from the Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) databases. Stepwise Cox analysis was employed to generate a signature. Then, we applied unsupervised clustering analysis to determine subclusters in GC based on URGs...

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice...

Dysregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of several metabolic disorders, including obesity, diabetes, and non-alcoholic fatty liver disease; however, the mechanisms controlling pathogenic metabolic disorders remain unclear. Transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) regulates adipogenic genes. The study showed that the expression level of C/EBPβ is post-translationally regulated by the deubiquitinase ubiquitin-specific protease 1 (USP1) and that USP1 expression is remarkably upregulated during adipocyte differentiation and in the adipose tissue of mice fed a high-fat diet (HFD)...

AIM: Doxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms. METHODS AND RESULTS: Mice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC...

Hypertensive nephropathy is second only to diabetes for the causation of chronic kidney disease worldwide. As the mortality and morbidity of hypertensive nephropathy keep increasing, it is important to elucidate its pathogenesis and develop new treatment strategies. In this study, an angiotensin II (Ang II)-induced renal cell system was established, and the expression of ubiquitin specific peptidase 1 (USP1) in human kidney (HK-2) cells was found to be regulated by Ang II treatment through quantitative RT-PCR and Western blot assay...

PURPOSE: Epstein-Barr virus-related lymphoepithelioma-like cholangiocarcinoma (EBV-LELCC), a subtype of intrahepatic cholangiocarcinoma (IHCC), is an extremely rare cancer. To date, only few cases have been reported. Therefore, more studies are needed to provide new insights into its clinicopathological characteristics and treatment. METHODS: We retrospectively collected data from 16 EBV-LELCC patients admitted to our hospital between January 2013 and February 2022...

The circadian clock is generated by a molecular timekeeping mechanism coordinating daily oscillations of physiology and behaviors in mammals. In the mammalian circadian clockwork, basic helix-loop-helix ARNT-like protein 1 (BMAL1) is a core circadian component whose defects lead to circadian disruption and elicit behavioral arrhythmicity. To identify previously unknown regulators for circadian clocks, we searched for genes influencing BMAL1 protein level by using a CRISPR/Cas9-based genome-wide knockout library...

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants...

The inhibitor of apoptosis protein survivin has a critical regulatory role in carcinogenesis and treatment tolerance in colorectal cancer (CRC). However, the targeted drugs for survivin protein are extremely limited. In the present research, we discovered that Tanshinone IIA (Tan IIA) played a dual regulatory role in inhibiting tumorigenesis and reversing 5-Fu tolerance via modulating the expression and phosphorylation of survivin in CRC cells. Mechanistically, Tan IIA suppressed the Akt/WEE1/CDK1 signaling pathway, which led to the downregulation of survivin Thr34 phosphorylation and destruction of the interaction between USP1 and survivin to promote survivin ubiquitination and degradation...