International Webinar on AID: A double edged sword for immunity and cancer
Studies from Prof. Basu’s lab has led to the unexpected conclusion that a significant portion of the mammalian genome transcribes noncoding RNAs (ncRNAs) and that the RNA exosome, a component of the cellular ncRNA surveillance machinery, rapidly decays some of the ensuing ncRNAs. Two questions have arisen: is there a biological function of ncRNA decay of such large and unprecedented nature, and what are the pathophysiological consequences of failure of ncRNA decay? Using B‑lymphocytes as a model system, Prof. Basu’s lab has pioneered studies demonstrating that surveillance and decay of the ncRNA transcriptome is an important mechanism for development and function of mammalian cells and when compromised, causes genomic instability, immune system dysregulation, and genetic alterations specific to cancer initiation.
In normal conditions, RNA surveillance pathway components orchestrate programmed immunoglobulin locus recombination by facilitating access of the DNA mutator AID to single strand DNA sequences stripped of inhibitory ncRNAs. Thus, Prof. Basu’s study provides the first evidence that RNA-decay machinery can be specifically targeted to a particular region of the mammalian genome to facilitate a defined biological function.
Prof. Basu discovered that when RNA surveillance pathways are suppressed by various genetic mutations, transcription associated DNA/RNA hybrids are not efficiently unwound leading to DNA mutagenesis and translocations. In pathophysiological conditions like in lymphomagenesis the RNA exosome subunit and cofactors are mutated; likewise, the developmental defects leading to Pontocerebellar Hypoplasia are caused by restricted ncRNA decay mediated by RNA exosome. Thus, Prof. Basu’s current studies highlight the relationship of RNA surveillance and transcription associated DNA mutagenesis in human diseases related to the immune and nervous systems.