RESUMEN
Transcription elongation is a highly dynamic and discontinuous process, which includes frequent pausing of RNA polymerase II (RNAPII). RNAPII complexes that stall persistently on a gene during transcription elongation block transcription and thus have to be removed. It has been proposed that the cellular pathway for removal of these DNA damage-independently stalled RNAPII complexes is similar or identical to the removal of RNAPII complexes stalled due to DNA damage. Here, we show that-consistent with previous data-DNA damage-independent stalling causes polyubiquitylation and proteasome-mediated degradation of Rpb1, the largest subunit of RNAPII, using Saccharomyces cerevisiae as model system. Moreover, recruitment of the proteasome to RNAPII and transcribed genes is increased when transcription elongation is impaired indicating that Rpb1 degradation takes place at the gene. Importantly, in contrast to the DNA damage-dependent pathway Rpb1 degradation of DNA damage-independently stalled RNAPII is independent of the E3 ligase Elc1. In addition, deubiquitylation of RNAPII is also independent of the Elc1-antagonizing deubiquitylase Ubp3. Thus, the pathway for degradation of DNA damage-independently stalled RNAPII is overlapping yet distinct from the previously described pathway for degradation of RNAPII stalled due to DNA damage. Taken together, we provide the first evidence that the cell discriminates between DNA damage-dependently and -independently stalled RNAPII.
Asunto(s)
Daño del ADN , ARN Polimerasa II/metabolismo , Elongación de la Transcripción Genética , Factores de Transcripción/fisiología , Elonguina , Complejo de la Endopetidasa Proteasomal/metabolismo , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/genética , UbiquitinaciónRESUMEN
Psoriasis is a common, disabling, chronic, relapsing, inflammatory disorder of the skin with a worldwide prevalence of 2-3 % in which adherence to treatment is often poor. The majority of individuals have limited disease that is being treated with topical medication according to existing guidelines. Adherence rates are lower for topical compared with systemic treatment. Low medication adherence is a major problem for patients with chronic disorders as it results in suboptimal treatment outcomes, increased risk for development of concomitant diseases, inefficient use of health resources and considerable losses to society. However, to date no adherence-enhancing intervention has been developed for psoriasis patients under topical treatment. In this article, we report the development of the topical treatment optimization program (TTOP). The TTOP intervention aims to improve the information given to the patients and to result in an engaged patient-physician relationship. Application of the TTOP intervention in daily clinical practice may lead to a significant increase of adherence and the successful management of psoriasis and other chronic skin disorders.
Asunto(s)
Cumplimiento de la Medicación/psicología , Educación del Paciente como Asunto/métodos , Psoriasis/tratamiento farmacológico , Administración Cutánea , Recolección de Datos , Femenino , Grupos Focales , Humanos , Masculino , Resultado del TratamientoRESUMEN
Medication adherence rates strongly depend on favorable disease outcomes. It is known that medication adherence rates are lower for topical treatment than for systemic treatment. However, to date no validated instrument for the assessment of adherence factors in topical treatment is available. The aim of this study was to develop a new questionnaire to assess adherence risk factors in topical treatment. The development of the Topical Therapy Adherence Questionnaire (TTAQ) and Patient Preference Questionnaire (PPQ) was based on a systematic literature review, and qualitative patient focus interviews and expert focus groups' input. The psychometric properties and comprehensibility of the TTAQ and PPQ were assessed in a feasibility study with 59 psoriasis patients. Our first preliminary results indicate that the TTAQ and PPQ are psychometrically sound and reliable measures for the assessment of factors influencing topical treatment adherence. The questionnaires are currently being further developed and various parameters (e.g., time point of assessment) are currently being tested in an exploratory pilot study with ca. 2,000 psoriasis patients receiving topical treatment in a European clinical trial. The use of the final versions of TTAQ and PPQ in clinical practice may facilitate the early identification of specific non-adherence factors in patients under topical treatment, which could enable designing and applying adherence-enhancing interventions according to the patient's individual needs.