Widespread displacement of DNA‐ and RNA‐binding factors underlies toxicity of arginine‐rich cell‐penetrating peptides

Lafarga, Vanesa; Sirozh, Oleksandra; Díaz-López, Irene; Galarreta, Antonio; Hisaoka, Misaru; Zarzuela, Eduardo; Boskovic, Jasminka; Jovanovic, Bogdan; Fernández-Leiro, Rafael; Muñoz, Jaime; Stoecklin, Georg; Ventoso, Iván; Fernández-Capetillo, Óscar

doi:10.15252/embj.2019103311

Cited by 25 publications

(26 citation statements)

References 57 publications

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“…The toxicity driven by arginine-containing DPRs has been demonstrated in both cell cultures [163,237,238] and in animal models [60,163,[239][240][241][242][243][244]. Recently, Lafarga and colleagues suggested that the presence of poly-PRs produces a generalized displacement of RNA-and DNA-binding proteins from chromatin and mRNA, impairing processes such as RNA transcription, translation, splicing, and degradation, or DNA replication and repair [9]. In fact, alterations in all these processes have been linked to ALS/FTD [245].…”

Section: Pathological Spreading Into Neurons: Mechanismsmentioning

confidence: 99%

“…External causative factors have also often been proposed for sALS, but none were totally confirmed, including exogenous environmental neurotoxins, heavy metals, dietary factors, physical exertion or trauma, or genetic factors [7,8]. It is worth noting that recently, arginine-rich cell-penetrating peptides have been associated with the onset of ALS, with a toxic effect linked to a widespread displacement of DNAand RNA-binding factors [9].…”

Section: Introductionmentioning

confidence: 99%

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The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

Pikatza-Menoio

Elicegui

Bengoetxea

et al. 2021

JPM

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

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Section: Pathological Spreading Into Neurons: Mechanismsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

Pikatza-Menoio

Elicegui

Bengoetxea

et al. 2021

JPM

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“…In addition, 21% of citrullinated proteins are classified as nucleotide binding proteins (PANTHER, PC00171). This is unsurprising when one considers that Arg-rich proteins are often responsible for binding to the net negatively charged backbone of DNA and RNA . One interesting example is the splicing factor U1 70K snRNP, which is citrullinated at Arg222.…”

Section: Resultsmentioning

confidence: 99%

“…This is unsurprising when one considers that Arg-rich proteins are often responsible for binding to the net negatively charged backbone of DNA and RNA. 39 One interesting example is the splicing factor U1 70K snRNP, which is citrullinated at Arg222. Arg222 is in a S/R/Erich region adjacent to the N-terminal RNA binding motif, and many studies have shown that the surrounding Ser residues can be phosphorylated to regulate alternative splicing, cell death, and autoantigenicity.…”

Section: Development and Validation Of Ionfindermentioning

confidence: 99%

A Streamlined Data Analysis Pipeline for the Identification of Sites of Citrullination

et al. 2021

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Citrullination is an enzyme-catalyzed post-translational modification (PTM) that is essential for a host of biological processes, including gene regulation, programmed cell death, and organ development. While this PTM is required for normal cellular functions, aberrant citrullination is a hallmark of autoimmune disorders as well as cancer. Although aberrant citrullination is linked to human pathology, the exact role of citrullination in disease remains poorly characterized, in part because of the challenges associated with identifying the specific arginine residues that are citrullinated. Tandem mass spectrometry is the most precise method for uncovering sites of citrullination; however, due to the small mass shift (+0.984 Da) that results from citrullination, current database search algorithms commonly misannotate spectra, leading to a high number of false-positive assignments. To address this challenge, we developed an automated workflow to rigorously and rapidly mine proteomic data to unambiguously identify the sites of citrullination from complex peptide mixtures. The crux of this streamlined workflow is the ionFinder software program, which classifies citrullination sites with high confidence on the basis of the presence of diagnostic fragment ions. These diagnostic ions include the neutral loss of isocyanic acid, which is a dissociative event that is unique to citrulline residues. Using the ionFinder program, we have mapped the sites of autocitrullination on purified protein arginine deiminases (PAD1−4) and mapped the global citrullinome in a PAD2-overexpressing cell line. The ionFinder algorithm is a highly versatile, user-friendly, and open-source program that is agnostic to the type of instrument and mode of fragmentation that are used.

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“…Poly-arginine PTD has also been used to generate ARF-CPPs containing mitochondria-targeting domain (aa 38-65) to show tumorsuppressive activities in multiple cancer types (Saito et al, 2013;Saito et al, 2016). The main challenge for future development of ARF-CPPs is to achieve an acceptable balance between anti-tumor efficacy and undesired toxicity, often seen in arginine-rich CPPs to dampen confidence for their eventual clinical applications (Li et al, 2017;Lafarga et al, 2021).…”

Section: Development Of Arf-based Therapeutic Strategies-therapeutic Peptidesmentioning

confidence: 99%

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

Kung

Weber

2022

Front. Cell Dev. Biol.

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Anti-tumorigenic mechanisms mediated by the tumor suppressor p53, upon oncogenic stresses, are our bodies’ greatest weapons to battle against cancer onset and development. Consequently, factors that possess significant p53-regulating activities have been subjects of serious interest from the cancer research community. Among them, MDM2 and ARF are considered the most influential p53 regulators due to their abilities to inhibit and activate p53 functions, respectively. MDM2 inhibits p53 by promoting ubiquitination and proteasome-mediated degradation of p53, while ARF activates p53 by physically interacting with MDM2 to block its access to p53. This conventional understanding of p53-MDM2-ARF functional triangle have guided the direction of p53 research, as well as the development of p53-based therapeutic strategies for the last 30 years. Our increasing knowledge of this triangle during this time, especially through identification of p53-independent functions of MDM2 and ARF, have uncovered many under-appreciated molecular mechanisms connecting these three proteins. Through recognizing both antagonizing and synergizing relationships among them, our consideration for harnessing these relationships to develop effective cancer therapies needs an update accordingly. In this review, we will re-visit the conventional wisdom regarding p53-MDM2-ARF tumor-regulating mechanisms, highlight impactful studies contributing to the modern look of their relationships, and summarize ongoing efforts to target this pathway for effective cancer treatments. A refreshed appreciation of p53-MDM2-ARF network can bring innovative approaches to develop new generations of genetically-informed and clinically-effective cancer therapies.

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Widespread displacement of DNA‐ and RNA‐binding factors underlies toxicity of arginine‐rich cell‐penetrating peptides

Cited by 25 publications

References 57 publications

The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

A Streamlined Data Analysis Pipeline for the Identification of Sites of Citrullination

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

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