Characterization of genetic modulators of PARP inhibitor sensitivity: molecular mechanisms and therapeutic implications

The clinical success of PARP 1/2 inhibitors (PARPi) prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of either the chromatin remodeler ALC1 or the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARPi. We show that ALC1 is important for mobilizing PARP1 from sites of DNA damage. Upon ALC1 deletion, PARPi treatment leads to enhanced PARP1 trapping and accumulation of double-strand breaks, which underlies the sensitivity of ALC1 KO to PARPi. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Strikingly, targeting ALC1 could bypass PARPi resistance caused by restoration of homologous recombination. Furthermore, we demonstrate that POLE4 loss affects replication speed leading to the accumulation of single-stranded DNA gaps behind replication forks upon PARPi treatment, due to impaired post-replicative repair. POLE4 knockouts elicit elevated replication stress signaling involving ATR and DNA-PK. Importantly We find POLE4 to act parallel to BRCA1 in inducing sensitivity to PARPi and counteracts acquired resistance associated with restoration of homologous recombination. Altogether, our findings establish ALC1 and POLE4 as a promising target to improve PARPi driven therapies and hamper acquired PARPi resistance

A vizuális kommunikáció alkotói részképességeinek online mérése 5–8. évfolyamon

My research aimed to explore the competence structure of visual communication, undoubtedly the most important visual skill cluster of our time. I also aimed to develop an innovative and authentic digital assessment tool to measure the four sub-skills of the creative domain of visual communication among students in grades 5-8. The first part of the dissertation presents the theoretical background of the research: it describes the concept of visual communication and its constituents, which supported the definition of the skill structure. It discusses the sensory basis of visual communication and, perceptual theory, and their role in the process of visual communication. A literature review summarises research on subskills and knowledge elements of the creative domain of visual communication. This review is followed by an introduction to the practice of assessing visual skills in international and national contexts and a review of some classic and contemporary models of visual skills. Based on previous research, I define the system of creative sub-skills to be investigated. On the basis of the testing study, I have developed a model of the creative subskills of visual communication that includes four skill clusters. Then the curricular framework of visual communication in Hungarian art education is explained. The third part of the thesis deals with the development of the assessment tool. After describing the research questions and hypotheses, I present the testing study that involved three phases of the development of an online test to verify the model. For each phase, the assessment tool, the research sample, the procedures, and the results are presented. Finally, research results are summarised and conclusions are drawn. For the first pilot study, a paper-based test was developed with a task structure designed to reveal the four sub-skills of the creative domain of visual communication. Task items were mapped to a sub-skill of visual communication ability. Two test variants of different levels of difficulty were designed. In this pilot study, a total of 117 students participated the assessment that took place in classrooms. For the second assessment, revised tasks were developed and posted in the GeoGebra Notes application. In this study, 73 pupils participated. The tasks were the same for all grades and the assessment was carried out in a school setting for all student groups. 311 pupils took part in the large-scale assessment, some of them solved the tasks at school and others at home (due to Covid restrictions). One of the main findings of these studies is, that valid assessment of visual skills can be performed using digital tests that simulate authentic use of visual language for 11-14-year-olds. A valid and reliable online test system and task bank were developed that is suitable for assessing important subskills of the creative domain of visual communication of upper secondary school students. The results confirmed that my hypothetical four-dimensional model of the subskills of the creative domain of visual communication is valid and may be used in art education for development and assessment. My results also contribute to the further development of the models of the Common European Framework of Reference for Visual Literacy and the Hungarian Visual Framework. In this way, they support the integration of visual learning and the knowledge equalizing potential of images into educational programmes in an increasingly image-dominated world