The dimeric deubiquitinase USP28 integrates 53BP1 and MYC functions to limit DNA damage.

DNA replication is a major source of endogenous DNA damage in tumor cells and a key target of cellular response to genotoxic stress. DNA replication can be deregulated by oncoproteins, such as transcription factor MYC, aberrantly activated in many human cancers. MYC is stringently regulated by the ubiquitin system - for example, ubiquitination controls recruitment of the elongation factor PAF1c, instrumental in MYC activity.

RNAPII-dependent ATM signaling at collisions with replication forks.

Deregulation of RNA Polymerase II (RNAPII) by oncogenic signaling leads to collisions of RNAPII with DNA synthesis machinery (transcription-replication conflicts, TRCs). TRCs can result in DNA damage and are thought to underlie genomic instability in tumor cells. Here we provide evidence that elongating RNAPII nucleates activation of the ATM kinase at TRCs to stimulate DNA repair.

Trim33 masks a non-transcriptional function of E2f4 in replication fork progression.

Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql.

USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer.

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway.

LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer.

The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids.

The Endothelial Landscape and Its Role in Von Hippel-Lindau Disease.

Von Hippel-Lindau disease (VHL) is a rare hereditary disease characterized by the predisposal to develop different types of highly vascularized tumors. VHL patients carry a mutation that causes partial lack of functional VHL protein (pVHL) in all cells, and a total lack thereof in cells harboring a second hit mutation. Absence of pVHL generates a prolonged state of pseudo-hypoxia in the cell due to accumulation of hypoxia inducible factor, an important transcription factor regulating pro-tumorigenic genes.

Ubiquitylation of MYC couples transcription elongation with double-strand break repair at active promoters.

The MYC oncoprotein globally affects the function of RNA polymerase II (RNAPII). The ability of MYC to promote transcription elongation depends on its ubiquitylation. Here, we show that MYC and PAF1c (polymerase II-associated factor 1 complex) interact directly and mutually enhance each other's association with active promoters.

Perspectives of lifespan extension: focus on external or internal resources?

and naked mole rats () are vivid examples of social mammals that differ from their relatives in particular by an increased lifespan and a large number of neotenic features. An important fact for biogerontology is that the mortality rate of (a maximal lifespan of more than 32 years, which is very large for such a small rodent) negligibly grows with age. The same is true for modern people in developed countries below the age of 60.

Driver mutations in USP8 wild-type Cushing's disease.

Background: Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.

Differential Oligomerization of the Deubiquitinases USP25 and USP28 Regulates Their Activities.

Deubiquitinases have emerged as promising drug targets for cancer therapy. The two DUBs USP25 and USP28 share high similarity but vary in their cellular functions. USP28 is known for its tumor-promoting role, whereas USP25 is a regulator of the innate immune system and, recently, a role in tumorigenesis was proposed.

Fbw7 and Usp28 - enemies and allies.

The Usp28 deubiquitinase antagonizes Fbw7-mediated turnover of multiple oncoproteins, including Myc, Jun, and Notch, and promotes tumorigenesis in the intestine. Our recent study reveals that Usp28 also counteracts autocatalytic ubiquitination of Fbw7, suggesting a complex role for Usp28 in the regulation of Fbw7 activity and tumor development.

Ubiquitin-Dependent Turnover of MYC Antagonizes MYC/PAF1C Complex Accumulation to Drive Transcriptional Elongation.

MYC is an unstable protein, and its turnover is controlled by the ubiquitin system. Ubiquitination enhances MYC-dependent transactivation, but the underlying mechanism remains unresolved. Here we show that MYC proteasomal turnover is dispensable for loading of RNA polymerase II (RNAPII).

Regulating Fbw7 on the road to cancer.

The F-box protein Fbw7 targets for degradation critical cellular regulators, thereby controlling essential processes in cellular homeostasis, including cell cycle, differentiation and apoptosis. Most Fbw7 substrates are strongly associated with tumorigenesis and Fbw7 can either suppress or promote tumor development in mouse models. Fbw7 activity is controlled at different levels, resulting in specific and tunable regulation of the abundance and activity of its substrates.

Usp28 counteracts Fbw7 in intestinal homeostasis and cancer.

The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin-dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a "piggyback" interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity.

Dual regulation of Fbw7 function and oncogenic transformation by Usp28.

Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates the turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-dependent substrate ubiquitination is antagonized by the Usp28 deubiquitinase. Here, we show that Usp28 preferentially antagonizes autocatalytic ubiquitination and stabilizes Fbw7, resulting in dose-dependent effects in Usp28 knockout mice.

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase.

Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models.

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer.

Colorectal cancer is the third most common cancer worldwide. Although the transcription factor c-MYC is misregulated in the majority of colorectal tumors, it is difficult to target directly. The deubiquitinase USP28 stabilizes oncogenic factors, including c-MYC; however, the contribution of USP28 in tumorigenesis, particularly in the intestine, is unknown.

Stabilization of Myc through heterotypic poly-ubiquitination by mLANA is critical for γ-herpesvirus lymphoproliferation.

Host colonization by lymphotropic γ-herpesviruses depends critically on expansion of viral genomes in germinal center (GC) B-cells. Myc is essential for the formation and maintenance of GCs. Yet, the role of Myc in the pathogenesis of γ-herpesviruses is still largely unknown.

PI3K-dependent phosphorylation of Fbw7 modulates substrate degradation and activity.

The Fbw7 tumor suppressor gene encodes the substrate recognition subunit of the SCF ubiquitin ligase, which targets for degradation a range of oncogenic proteins in a phosphorylation-dependent manner. Substrate phosphorylation is thought to be the main mechanism that ensures timely destruction of Fbw7 substrates. We show here that PI3K dependent phosphorylation of Fbw7 stimulates its ability to ubiquitinate and degrade its substrates.

Ubiquitylation of the amino terminus of Myc by SCF(β-TrCP) antagonizes SCF(Fbw7)-mediated turnover.

The SCFFbw7 ubiquitin ligase mediates growth-factor-regulated turnover of the Myc oncoprotein. Here we show that SCFβ-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability. SCFFbw7 and SCFβ-TrCP can exert these differential effects through polyubiquitylation of the amino terminus of Myc.

Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma.

In human neuroblastoma, amplification of the MYCN gene predicts poor prognosis and resistance to therapy. In a shRNA screen of genes that are highly expressed in MYCN-amplified tumors, we have identified AURKA as a gene that is required for the growth of MYCN-amplified neuroblastoma cells but largely dispensable for cells lacking amplified MYCN. Aurora A has a critical function in regulating turnover of the N-Myc protein.

Fbw7 and Usp28 regulate myc protein stability in response to DNA damage.

The cellular levels of the Myc oncoprotein are critical determinants of cell proliferation, cell growth and apoptosis and are tightly regulated by external growth factors. Levels of Myc oncoprotein also decline in response to intracellular stress signals such as DNA damage. We show here that this decline is in part due to proteasomal degradation and that it is mediated by the Fbw7 ubiquitin ligase.

The ubiquitin-specific protease USP28 is required for MYC stability.

The MYC proto-oncogene encodes a transcription factor that has been implicated in the genesis of many human tumours. Here, we used a bar-code short hairpin RNA (shRNA) screen to identify multiple genes that are required for MYC function. One of these genes encodes USP28, an ubiquitin-specific protease.

The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation.

The Myc oncoprotein forms a binary activating complex with its partner protein, Max, and a ternary repressive complex that, in addition to Max, contains the zinc finger protein Miz1. Here we show that the E3 ubiquitin ligase HectH9 ubiquitinates Myc in vivo and in vitro, forming a lysine 63-linked polyubiquitin chain. Miz1 inhibits this ubiquitination.