RNA dependent DNA damage response

Genetic information stored in DNA is continuously exposed to endogenous or exogenous damaging factors. Efficient DNA damage repair is a fundamental process for every living organism. The accumulation of DNA damage affects cellular viability and leads to a variety of diseases, particularly cancer. Therefore, understanding of the molecular mechanisms necessary for DNA damage repair is of great importance. A myriad of repair factors targets double-strand breaks (DSBs) by non-homologous end joining (NHEJ) or homologous recombination (HR) pathways. However, the relevance of RNA for the DNA damage response (DDR) is currently not understood and the impact of transcription on genome stability and the role of RNA binding factors as well as function of small RNA (DDRNA) remain enigmatic. My research aims to elucidate molecular mechanism of RNA dependent DDR and its relevance to cancer. We pay special attention to various types of small non-coding RNA and their roles within DDR pathway as well as acting signalling molecules.

Mammalian cells employ small RNAs (sRNAs) molecules to regulate gene expression in a pathway known as RNA interference (RNAi). Transfer RNAs (tRNAs) are essential for translation but also serve as a source for tRNA-derived small RNAs (tsRNAs). We discovered that the endoribonuclease Dicer, a critical player in canonical RNAi, associates with actively transcribed tRNA genes, binds to alternatively folded tRNAs and processes them into tsRNAs. Dicer-dependent tsRNAs target the introns of many protein coding genes and long non-coding RNAs, leading to degradation of their nascent RNA. Importantly, tsRNAs target genes are significantly associated with disease phenotypes underpinning the biological importance of this pathway. We propose a mechanism for intronic gene silencing that is distinct from well-known post-transcriptional or transcriptional gene expression regulation. We employ synthetic tsRNA targeting oncogenes to suppress aggressive cancer phenotype, which has promising applications in future cancer therapies (patent filed by Cancer Research UK). We wish to understand why and how is intronic gene silencing de-regulated in cancer cells and what is the potency of using synthetic tsRNA in cancer cells in order to supress their oncogenic phenotype.