ADP-ribosyltransferases, an update on function and nomenclature

Data de publicació electrónica: 29-07-2021ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes

Presencia de Sternocoelis fusculus (Schmidt, 1888) en la Comunidad Autónoma de Madrid (Centro de España) (Coleoptera, Histeridae, Haeteriinae).

Sternocoelis fusculus (Schmidt, 1888) (Coleoptera, Histeridae, Haeteriinae) is recorded for the first time from the Autonomous Community of Madrid (Central Spain).Se cita por primera vez Sternocoelis fusculus (Schmidt, 1888) (Coleoptera, Histeridae, Haeteriinae) de la Comunidad Autónoma de Madrid (Centro de España)

Immunomodulatory roles of PARP-1 and PARP-2: impact on PARP-centered cancer therapies

Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which post-translationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair. However, a cancer is not just made up of cancer cells and the tumor microenvironment also includes multiple other cell types, particularly stromal and immune cells. Interactions between these cells-cancerous and non-cancerous-are known to either favor or limit tumorigenesis. In recent years, an important role of PARP-1 and PARP-2 has been demonstrated in different aspects of the immune response, modulating both the innate and adaptive immune system. It is now emerging that PARP-1 and PARP-2 may not only impact cancer cell biology, but also modulate the anti-tumor immune response. Understanding the immunomodulatory roles of PARP-1 and PARP-2 may provide invaluable clues to the rational development of more selective PARP-centered therapies which target both the cancer and its microenvironment.This research was funded by The Fundación Científica de la Asociación Española Contra el Cáncer (AECC), grant number PROYEI6018YÉLA, and the Spanish Ministerio de Economía, Industria y Competitividad, grant number SAF2017-83565-R

Crecimiento y caracterización de cristales de alcanoatos de plomo (II): Di-octa, Di-nona y Di-decanoato.

Single crystals oflead (n) n-octa (Pb(C9)2), n-nona (Pb(C9)2), and n-decanoate (Pb(C10)2 have been obtained by using a silica gel technique. These crystals were identified by polarizing light microscopy, x-ray diffiaction. Raman spectroscopy, and scanning electron microscopy. The crystals show polyhedral morphology bounded by flat faces (001) and nonflat striated faces. In the (001) faces, cleavage lines can be observed . This cleavage can be related with bylayer structure of these compounds. In the cases of Pb(C9)2, and Pb(C10)2 two kinds of crystals with different intemal angle cleavage have been found. The first one with 90º and the second one with 120º, aproximately. This fact can be explained attending to polymorphism and polytypism in the lead (ll) alkanoates serie. X-ray and Rarnan spectroscopy data of single crystals are compared with the polycrystalline samples ones. [RESUMEN] Se han obtenido monocristales de tres miembros de la serie de alcanoatos de plomo (II)(a partir de aquí, Pb[CH3(CH2)n-2COO]2 ó Pb(Cn)2 utilizando la técnica de crecimiento en geles en un sistema de doble difusión-reacción. Los cristales obtenidos han sido identificados mediante microscopía de luz polarizada, difRacción de rayos X, espectroscopía Raman y microscopía electrónica de barrido. Los cristales de los tres compuestos muestran morfologías poliédricas y en algún caso desarrollos dendríticos, estando formados por caras planas (001) y caras prismáticas estriadas. Estos cristales presentan exfoliación basal (001) perfecta, que puede explicarse en función de la estructura en capas que presentan este tipo de compuestos. En el caso de los alcanoatos de Pb(C9)2 y de Pb(C10)2 crecidos en geles se pueden diferenciar dos tipos de cristales en función del ángulo existente entre las líneas de exfoliación. Los datos de rayos X y de espectroscopía Raman de los cristales de los tres alcanoatos estudiados se comparan con los de las muestras policristalínas obtenidas por cristalización

Poly(ADP-Ribose) Polymerases: New Players in the Pathogenesis of Exocrine Pancreatic Diseases.

The poly(ADP-ribose) polymerase (PARP) enzymes were initially characterized as sensors of DNA breaks but are now known to play key roles not only in the DNA damage response but also in regulating numerous molecular processes, such as gene transcription. Furthermore, these polymerases have emerged as key players in the pathogenesis of multiple diseases, providing promising therapeutic targets for pathologies such as cardiovascular disorders, neurodegenerative diseases, and cancer. In recent years, PARPs have been implicated in the pathogenesis of pancreatitis and pancreatic cancer, and PARP inhibition has been proposed as a valuable strategy for treating these two important gastrointestinal tract disorders. For instance, in preclinical mouse models, pancreatitis was significantly attenuated after genetic or pharmacological PARP inactivation, and several clinical trials have demonstrated promising responses to PARP inhibitors in pancreatic cancer patients. In this review, we summarize the current understanding of PARP functions in these two dismal pathologies and discuss the next steps necessary to determine whether PARP inhibitors will finally make the difference in treating pancreatitis and pancreatic cancer successfully

Reduced tumor burden through increased oxidative stress in lung adenocarcinoma cells of PARP-1 and PARP-2 knockout mice.

Lung cancer (LC) is currently a major leading cause of cancer deaths worldwide. Poly(ADP-ribose) polymerases (PARP)-1 and -2 play important roles in DNA repair and other cell functions. Oxidative stress triggers autophagy and apoptosis. PARP inhibitors are currently used as anticancer strategies including LC. We hypothesized that inhibition of either PARP-1 or -2 expressions in the host animals influences tumor burden through several biological mechanisms, mainly redox imbalance (enhanced oxidative stress and/or decreased antioxidants, and cell regulators) in wild type (WT) lung adenocarcinoma cells. Compared to WT control tumors, in those of Parp-1(-/-) and Parp-2(-/-) mice: 1) tumor burden, as measured by weight, and cell proliferation rates were decreased, 2) oxidative stress levels were greater, whereas those of the major antioxidant enzymes were lower especially catalase, 3) tumor apoptosis and autophagy levels were significantly increased, and 4) miR-223 and nuclear factor of activated T-cells (NFAT)c-2 expression was decreased (the latter only in Parp-1(-/-) mice). Furthermore, whole body weight gain at the end of the study period also improved in Parp-1(-/-) and Parp-2(-/-) mice compared to WT animals. We conclude that PARP-1 and -2 genetic deletions in the host mice induced a significant reduction in tumor burden most likely through alterations in redox balance (downregulation of antioxidants, NFATc-2 and miR223, and increased oxidative stress), which in turn led to increased apoptosis and autophagy. Furthermore, tumor progression was also reduced probably as a result of cell cycle arrest induced by PARP-1 and -2 inhibition in the host mice. These results highlight the relevance of the host status in tumor biology, at least in this experimental model of lung adenocarcinoma in mice. Future research will shed light on the effects of selective pharmacological inhibitors of PARP-1 and PARP-1 in the host and tumor burden, which could eventually be applied in actual clinical settings.The study has been funded by Instituto de Salud Carlos-III: CIBERES, FIS 11/02029, FIS 14/ 00713 and Fundació La Marató de TV3: 2013 e4130

Attenuation of muscle damage, structural abnormalities, and physical activity in respiratory and limb muscles following treatment with rucaparib in lung cancer cachexia mice

Overactivation of poly (ADPribose) polymerases (PARPs) is involved in cancer-induced cachexia. We hypothesized that the PARP inhibitor rucaparib may improve muscle mass and reduce damage in cancer cachexia mice. In mouse diaphragm and gastrocnemius (LP07 lung adenocarcinoma) treated with PARP inhibitor (rucaparib,150 mg/kg body weight/24 h for 20 days) and in non-tumor control animals, body, muscle, and tumor weights; tumor area; limb muscle strength; physical activity; muscle structural abnormalities, damage, and phenotype; PARP activity; and proteolytic and autophagy markers were quantified. In cancer cachexia mice compared to non-cachexia controls, body weight and body weight gain, muscle weight, limb strength, physical activity, and muscle fiber size significantly declined, while levels of PARP activity, plasma troponin I, muscle damage, and proteolytic and autophagy markers increased. Treatment with the PARP inhibitor rucaparib elicited a significant improvement in body weight gain, tumor size and weight, physical activity, muscle damage, troponin I, and proteolytic and autophagy levels. PARP pharmacological inhibition did not exert any significant improvements in muscle weight, fiber size, or limb muscle strength. Treatment with rucaparib, however, improved muscle damage and structural abnormalities and physical activity in cancer cachexia mice. These findings suggest that rucaparib exerts its beneficial effects on cancer cachexia performance through the restoration of muscle structure.Project “FI19/00001” funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. María Pérez-Peiró was a recipient of a predoctoral fellowship from FIS Contratos Predoctorales de Formación en Investigación en Salud. The current research has been supported by project FIS 18/00075 funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union and CIBERES 2021 funded by Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation; Spanish Respiratory Society (SEPAR), SEPAR 2018. The Yélamos lab is funded by the Spanish Ministry of Science and Innovation (grant PID2020-112526RB-I00 funded by MCIN/AEI/10.13039/501100011033)