|
|
Molecular analysis of Cornelia de Lange syndrom
Vokáčová, Markéta ; Schierová, Michaela (advisor) ; Jedličková, Jana (referee)
Cornelia de Lange syndrome is a rare, very heterogeneous, genetic disorder classified as a cohesinopathy. It is caused by mutations in genes that encode proteins of the cohesin complex or its regulators. So far, 5 major genes, whose defects are responsible for the syndrome, have been discovered. The mutated gene determines the type of heredity and, above all, the extent of the pathology. Due to dysfunction of the cohesin complex, not only the cohesion of sister chromatids is impaired, but also the regulation of gene expression and the repair of DNA double-strand breaks. Knowledge of molecular aspects of the disease has been enhanced by ongoing experiments with animal models of Cornelia de Lange syndrome, cell cultures from patients, and the yeast Saccharomyces cerevisiae. The detailed analysis of the biological functions of the cohesin complex may help to develop therapeutic methods. Keywords: Cornelia de Lange syndrome, cohesin complex, cohesinopathy, transcriptome change, genome integrity, topologically associating domains, NIPBL
|
|
|
A DNA double-strand break repair and it's disorders with a relationship to the cancerogenesis
Komžák, Josef ; Ševčík, Jan (advisor) ; Vopálenský, Václav (referee)
The DNA-double strand break (DSB) repair has an essential importance for the genomic integrity maintenance. The main DSB repair pathways are homologous recombination (HR), non-homologous end joining (NHEJ) and single-strand annealing (SSA). The most important protein factors contributing to the maintenance of genomic integrity by direct participation in DSB repair are MRN, ATM, Rad51, BRCA1/2 and PALB2 in the case of HR; Ku70/80 DNA-PKcs, XRCC4 and DNA ligase IV in the case of NHEJ and Msh2-Msh3 and Rad1- Rad10 in the case of SSA. If mutated, these proteins can cause the inability to repair DNA lesions leading to a malignant transformation. The predominant phenotype manifestation of BRCA1/2 inactivation is the hereditary breast and/or ovarian cancer (HBOC). Mutations in ATM have been described as a cause of ataxia telangiectasia and inactivation of NBN gene (Nbs1 protein) causes the Nijmegen breakage syndrome. Other syndromes connected with defects in a DSB repair pathways are Fanconi anemia and Werner syndrome. Detail knowledge of DSB repair process is a mandatory for diagnostics and effective therapy of a number of malignances. An example of practical and clinically relevant utilization of current knowledge about the DSB repair process is the concept of a synthetic lethality as a specific therapy. This...
|
guest ::
