Final Report Summary - BFTERRA (Biogenesis and Functions of Telomeric Repeat-containing RNA)
Contrarily to messenger RNAs that function by conveying sequence information for protein synthesis, noncoding RNAs (ncRNAs) directly influence a multitude of crucial cellular processes including transcription, heterochromatin establishment and genome stability. De-regulation of ncRNA homeostasis is associated to a number of disease conditions including cancer, a notion that highlights the centrality of ncRNAs in cellular and organismal biology. Yet, the functions associated to the noncoding transcriptome and how it is regulated in cells continue to be largely mysterious. One such ncRNA is TERRA (TElomeric Repeat-containing RNA), a chromatin-associated long ncRNA produced by RNA polymerase II-mediated transcription of telomeres, the protective structures located at the end of linear eukaryotic chromosomes. Using a combination of cellular and molecular biology, biochemistry, genetics and dynamic light microscopy applied to cultured mammalian cells and the fission yeast Schizosaccharomyces pombe we have increased our understanding of the cellular roles and regulation of TERRA. Besides discovering novel pathways of regulation of TERRA cellular levels, we have also shown that TERRA promotes telomere length maintenance in different organisms and its regulation is directly linked to proliferation of cancer cells. In a parallel research project, we have discovered a novel enzyme, Mpn1, which is responsible of stabilizing the spliceosomal small nuclear RNA U6. Mutations in the MPN1 gene are associated Clericuzio-type poikiloderma with neutropenia, a rare genodermatosis whose molecular origin was completely unknown. Our studies set TERRA and telomere transcription as key players in crucial aspects of telomere biology directly connected to cancer etiology and should pave the way for the development of novel therapeutic approaches to cure cancer and poikiloderma with neutropenia.