The Cross Talk among Autophagy, Ubiquitination, and DNA Repair: An Overview

Cellular plasticity is modulated by protein posttranslational modifications, which act on most intracellular pathways. Ubiquitination is a versatile posttranslational modification (PTM) that influences protein fate, controlling their degradation or modulating their activity and subcellular localization. The ubiquitin proteasome system, UPS, and the autophagic pathway are the main degradative intracellular machineries, which rely on ubiquitination for their activation and/or the selective recycling of proteins and organelles. Recent findings indicate that the cross talk between UPS and autophagy plays a key role in controlling DNA repair pathways. Even being a cytoplasmic process, it is now clear that autophagy can directly impact on the correct activation of DNA repair. Of note, defects on autophagy are related to the impairment of homologous recombination repair and to an increase of the nonhomologous end joining repair activity. These evidences give new insights into the molecular processes underlying the DNA damage response and provide further explanation for the tumorigenesis associated with autophagy impairment. Moreover, these findings introduce new examples of synthetic lethality between autophagy and DNA repair genes and lead to the possible development of target therapies for tumors with defective autophagy

AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity

Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway(1,2). Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis

RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4

Autophagy is a key degradative pathway coordinated by external cues, including starvation, oxidative stress, or pathogen detection. Rare are the molecules known to contribute mechanistically to the regulation of autophagy and expressed specifically in particular environmental contexts or in distinct cell types. Here, we unravel the role of RUN and FYVE domain–containing protein 4 (RUFY4) as a positive molecular regulator of macroautophagy in primary dendritic cells (DCs). We show that exposure to interleukin-4 (IL-4) during DC differentiation enhances autophagy flux through mTORC1 regulation and RUFY4 induction, which in turn actively promote LC3 degradation, Syntaxin 17– positive autophagosome formation, and lysosome tethering. Enhanced autophagy boosts endogenous antigen presentation by MHC II and allows host control of Brucella abortus replication in IL-4–treated DCs and in RUFY4-expressing cells. RUFY4 is therefore the first molecule characterized to date that promotes autophagy and influences endosome dynamics in a subset of immune cells

TFG: a novel regulator of ULK1-dependent autophagy

TRK-fused gene (TFG) is a protein implicated in multiple neurodegenerative diseases and oncogenesis. We have recently shown that, under starvation conditions, TFG contributes to spatial control of autophagy by facilitating Unc-51 like autophagy activating kinase 1 (ULK1)-microtubule-associated protein 1 light chain 3 gamma (MAP1LC3C) interaction to modulate omegasome and autophagosome formation. Defective TFG-mediated autophagy could thus be postulated as a possible contributor to ontogenesis or progression of TFG-related diseases

The Close Interconnection between Mitochondrial Dynamics and Mitophagy in Cancer

Recent decades have revealed the shape changes of mitochondria and their regulators to be main players in a plethora of physiological cell processes. Mitochondria are extremely dynamic organelles whose highly controlled morphological changes respond to specific and diverse pathophysiological needs. Thus, their qualitative control is crucial for the determination of cell function and fate. Moreover, ever-new metabolic changes, mainly attributable to mitochondrial (dys)functions, are strongly connected to cancer and its microenvironment. For this reason, the aspects controlling mitochondria activity and status are in the oncological spotlight. In this review, we elucidate the most intriguing discoveries related to two apparently independent but strictly interconnected processes crucial for the organelle functionality and fate, mitochondrial dynamics, and mitophagy. We will mostly focus on their metabolic interconnections and regulations that can causally foster a tumoral context

Chapter The Cross Talk among Autophagy, Ubiquitination, and DNA Repair: An Overview

Cellular plasticity is modulated by protein posttranslational modifications, which act on most intracellular pathways. Ubiquitination is a versatile posttranslational modification (PTM) that influences protein fate, controlling their degradation or modulating their activity and subcellular localization. The ubiquitin proteasome system, UPS, and the autophagic pathway are the main degradative intracellular machineries, which rely on ubiquitination for their activation and/or the selective recycling of proteins and organelles. Recent findings indicate that the cross talk between UPS and autophagy plays a key role in controlling DNA repair pathways. Even being a cytoplasmic process, it is now clear that autophagy can directly impact on the correct activation of DNA repair. Of note, defects on autophagy are related to the impairment of homologous recombination repair and to an increase of the nonhomologous end joining repair activity. These evidences give new insights into the molecular processes underlying the DNA damage response and provide further explanation for the tumorigenesis associated with autophagy impairment. Moreover, these findings introduce new examples of synthetic lethality between autophagy and DNA repair genes and lead to the possible development of target therapies for tumors with defective autophagy

Should I stay or should I go? Spatio-temporal control of cellular anchorage by hematopoietic factors orchestrates tumor metastatic cascade

Abstract The term “metastatic cascade” defines a process whereby few tumor cells complete a sequence of steps to leave the primary tumor to reach one or more sites elsewhere in the body, usually through the bloodstream to develop one or several metastases. Due to the nature and plasticity of cancer, unfortunately no specific and functional anti-metastatic drugs are available. In this Commentary, we are highlighting how four essential factors are able to induce adhesion-to-suspension transition (herein referred to as AST) in human cancer cells and how this process may play a key role in tumor metastasis. We further underlined the potential role of hematopoietic transcriptional regulators in reprogramming anchorage dependency of cells, supporting the possible targeting of AST factors as promising therapeutic strategy to overcome metastasis in solid tumor cells