Role of dyskerin as a tumor suppressor in human cancer

In humans, point mutations in the DKC1 gene encoding dyskerin cause the rare skin, mucosal and bone marrow failure syndrome termed X-linked dyskeratosis congenita (DC) characterized also by an increased susceptibility to cancer. Dyskerin is a nucleolar protein that carries out two separate functions. One is to modify specific uridine residues of ribosomal RNA and small nuclear RNA by converting them to pseudouridine and the other is to stabilize the telomerase RNA component (TERC), allowing the proper function telomerase enzymatic complex. The mechanisms leading to cancer in DC is still unknown but studies in the hypomorphic DKC1 mutant mice indicate that a defect in ribosome function has, at least in part, a direct causal effect through the modification of proper mRNA translation. Altogether, data obtained in DC patients and in DKC1m hypomorphic mice suggest that dyskerin may behave as a tumor suppressor, promoting cancer when not functioning properly. A relevant question that remains unanswered is whether the normal function of dyskerin can be altered and thus promote cancer not only in the rare X-linked DC and in experimentally generated DC mouse models, but more in general in human cancer. Our preliminary data on dyskerin mRNA and TERC levels and rRNA pseudouridylation indicate that dyskerin expression and functions are tightly related each other and highly reduced in a subset of human breast carcinomas. Moreover, breast carcinomas with reduced dyskerin expression are characterized by a distinct clinical outcome. This scenario is compatible with dyskerin behaving as a tumor suppressor in a subset of breast carcinomas. This research project is aimed to define if and through which mechanisms this actually occurs in human breast carcinomas as well as in other types of human cancers. To do this we plan to proceed experimentally on one side studying how dyskerin functional impairment can influence the translation of genes involved in neoplastic transformation and progression in vitro and on the other side studying DKC1 gene mutations, epigenetic modifications and expression as well as dyskerin function and mRNA translation in primary tumors relevant for human pathology such as breast and lung carcinomas and B cell lymphomas. The results obtained will define the contribution of the alterations of dyskerin function in human tumor pathology.