According to our cloning strategy, we obtained recombinant proteins derived from PARP-1 protein conesponding to the first Zn finger (Znl), the second finger of Zn (Zn2), the third finger of Zn (Zn3) at region DB-WRG-CAT and region CAT-WRG. In order to demonstrate that Znl and Zn2 interact with simple-stranded DNA (ssDNA) we used Electrophoretic mobility shift assay (EMSA). Our results suggest that Znl and Zn2 have the ability to bind to ssDNA with a high preference for poly (dA) poly (T) and poly (dC). Among the probes single-stranded DNA, Zn3 has shown an affinity for poly (T), poly (dG) and poly (dC). Remarkably, Zn3 showed strong binding to RNA probes. This result allows us to suggest a role Zn3 in the transcription process. The enzyme could be in contact with RNA-DNA hybrid during the process. However, the precise role of Zn3 remains to be established. The fingers of Znl, Zn2 and Zn3 and the fragment WGR-CAT showed no affinity for double-stranded DNA (dsDNA). Furthermore, we cloned a region of 60 amino acids located between the BRCT domain and WRG domain of PARP-1 protein, we named it DB region. The fragment DB-WRG-CAT showed a strong affinity for dsDNA. This result suggests that the region DB is responsible for the interaction of PARP-1 with dsDNA. To determine if PARP-1 binds to a structure of ssDNA and dsDNA, and to demonstrate whether this interaction can activate the enzyme, we constructed various DNA structures that contain a loop of adenine or thymidine. Our results suggest that the DNA that contains a junction between single and double strand acts as a potential activator of PARP-1. Finally, we propose a model for understanding the interaction of PARP-1 with DNA which is founded in many biological processes.

Étude sur l'interaction entre les différents domaines de la PARP-1 et diverses structures de l'ADN

PARP-1 is a highly conserved modular enzyme, which structure includes: 1) an aminoterminal DNA binding domain (DBD), containing a nuclear localization signal and three zinc fingers Znl, Zn2 and the recently discovered Zn3; these three fingers act as molecular sensor of DNA breaks; 2) a central régulateur domain containing a BRCT motif and sites acceptors of poly (ADP-ribose) to inactivate PARP-1 (automodification reaction); and 3) a carboxy-terminal domain containing the catalytic active site. In our study, after cloning different recombinant proteins by PCR, we have done tests of poly (ADP) ribosylation of raw cell extracts. In addition, we have done gel retardation assay (EMSA) with oligonucleotides to evaluate the interactions of peptides corresponding to fragments of the DBD domain, with these oligonucleotides in an attempt to explain how activation of the enzyme occurs.

PARP-1 : interaction du domaine de liaison à l'adn avec des oligonucléotides simple brin

Les nouvelles poly(ADP-ribose)polymérases : vers une famille de protéines associées au maintien de l'intégrité génomique ?

Fréquente et invalidante chez les personnes souffrant de schizophrénie, la fatigue reste, cependant, peu explorée dans cette pathologie. Le manque de connaissances et de données dans la littérature concernant ce symptôme complexe en limite l’évaluation clinique et la prise en considération dans les approches thérapeutiques. L’objectif de ce débat d’idées est de discuter les mécanismes et origines physiopathologiques de la fatigue dans la schizophrénie (en distinguant notamment les concepts de fatigue primaire et secondaire), d’en identifier les implications cliniques et fonctionnelles et d’explorer des traitements potentiels. Les travaux antérieurs dans la schizophrénie étudient principalement la fatigue en tant que Trait, par des auto-questionnaires, mais cette approche observationnelle ne permet pas d’évaluer ce symptôme dans des conditions de vie réelle au cours desquelles des hauts niveaux de fatigue peuvent survenir et varier rapidement. Nous proposons de considérer la fatigue – État apparaissant par exemple après une période d’activité cognitive prolongée (i.e. la fatigue mentale). Explorer les liens entre fatigue et symptômes négatifs dans la schizophrénie apparaît, de fait, pertinent. La variable « fatigue » pourrait, ainsi, contribuer à une meilleure compréhension de ces symptômes par le biais de travaux étudiant l’effet de la fatigue aiguë sur l’intention d’effort et les comportements. L’approche multidimensionnelle des aspects de la fatigue dans la schizophrénie permettra de proposer de nouvelles voies thérapeutiques pharmacologiques et non-pharmacologiques. Des interventions ciblant les composantes cognitives et celles relatives à la performance de la fatigue, à travers des protocoles en double tâche (exercice aérobie/entraînement cognitif), pourraient alors offrir d’intéressantes perspectives pour diminuer la fatigue dans la schizophrénie et en limiter le retentissement fonctionnel négatif. Despite being one of the most common complaints of people with schizophrenia, fatigue remains largely unexplored in this population. The lack of knowledge regarding this complex symptom makes it often underdiagnosed and undertreated in schizophrenia. The aim of this brief perspective review is to outline the potential origins (distinguishing primary and secondary fatigue) and consequences of fatigue and to explore some potential treatments in this population. The current literature in schizophrenia has mainly investigated fatigue as a trait, using a self-administered questionnaire. Beyond this observational approach, which does not allow to capture the symptom in real life situations where high levels of fatigue can emerge rapidly, we propose to consider the state level of fatigue, for instance occurring after a prolonged period of cognitive activity (i.e. mental fatigue). We elaborate on the potential relationships between mental fatigue and negative symptoms of schizophrenia and propose some research avenues to test the effects of acute fatigue on effort intentions and behaviours. The consideration of the multidimensional aspects of fatigue will allow to move beyond the sole pharmacological approach to treat fatigue in schizophrenia. Targeting the cognitive as well as the performance components of fatigue through interventions such as concomitant aerobic exercise - mental training offers attractive prospects to reduce fatigue in this population and minimize its functional negative impact. 

Vers une meilleure compréhension de la fatigue dans la schizophrénie

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Les nouvelles poly(ADP-ribose)polymérases : vers une famille de protéines associées au maintien de l'intégrité génomique ?

Vers une meilleure compréhension de la fatigue dans la schizophrénie