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RNA binding proteins (RBPs)

     RBPs are truly multifaceted proteins that play critical roles in RNA biogenesis, function, stability, cellular localization and transport by influencing their structure and interactions. A great number of RBPs are produced in eukaryotic cells, each enclosing a unique protein-to-protein interaction characteristic and RNA-binding activity. The remarkable diversity of RBPs have increased during evolution; allowing eukaryotic cells to give rise to unique RNP for each RNA by utilizing a wide range of exclusive combinations. ZFP36L1 belongs to a zinc finger family of RNA binding protein, which are characterised by CCCH class of tandem zinc finger proteins. This zinc finger protein family recognises conserved Adenylate Uridylate rich elements (AREs) present in 3'untranslated regions (UTRs) of mRNAs and promote their degradation, ultimately leading to mRNAs decay. ZFP36 family are implicated in regulation of many ARE containing mRNAs, which encode for proteins related to development, cell differentiation, inflammation and apoptosis. Loss of ZFP36 family member expressions results in deregulation of several mRNA targets that have prominent role in regulation of oncogenes and tumour suppressor genes. Although, in the recent years with technology developing rapidly, there are RBPs where little about their functional relevance is known. Genetic and biochemical experiments alongside the use of bioinformatic analysis has revealed sequenced genomes which need to be explored further to fill the gaps in knowledge. Up till date, there has been an impressive progress in the discovery of RNA-binding motifs and RBPs mode of interaction with RNA however their structure, the location of these proteins and the precise arrangements of these proteins in the complex RNA assemblies of distinct cellular compartments is still a mystery.

DNA damage response and human diseases

     The health and physiology of an organism is the result of continuous battle between the mechanisms that induce damage to DNA and those in charge of its repair. Despite its secure location and apparent protection, the integrity of DNA, the genetic material faces threats daily. The modalities and mechanisms are very varied, including different forms of structural modification and functional alteration of the molecular players of DNA damage response. Importantly, most cancers have a greater dependency on particular DDR mechanisms, due to the loss of one or more DDR capabilities during the oncogenesis. By understanding and identifying these dependencies, we can use precision medicine approaches and targeted DDR inhibitors to maximise DNA damage and selectively kill cancer cells. Two key factors influence the DDR – the type of DNA damage, and when the damage occurs during the cell cycle. While some types of DNA damage are repaired quickly, complex DNA damage takes longer to repair. This provides a truly targeted approach to cancer treatment with the potential to improve patient outcomes across multiple tumour types. Oncogene activation promotes cell proliferation by interfering with the regulatory pathways of cell that results in alterations of replication process such as replication fork rates, frequent replication initiation or origin firing, premature entry in S phase, lead to replication stress. Experimental studies have shown increased rate of mutations in DDR genes in the tumour cells, showing a clear relationship between replication stress and tumour progression. To counteract replication stress, cells have evolved sophisticated cell cycle checkpoints pathways and DNA damage repair pathways that are present at well-defined points to resolve DNA damage and ensures completion of replication with high fidelity. While G1 checkpoints prevent occurrence of any faulty DNA replication to occur, G2/M checkpoints prevent entering of damaged DNA into mitosis. During S phase of cell cycle, multiple intra-S- phase checkpoints are incorporated with multiple pathways to ensure error-free replication and prevent genome instability. Oncogene-induced replication stress is a tumour specific vulnerability target and served as a rationale for the clinical development of inhibitors targeting the DDR kinases including CHK1, ATR, ATM and WEE1. Overall, targeting cancer-specific vulnerabilities in DNA repair has been shown to improve response rates, increase overall survival and limit toxic side effects in patients. We pioneer in genome engineering research at the University and will continue to push the boundaries of our knowledge in this important area to improve the understanding of anticancer mechanisms.

CRISPR/Cas diagnostics for biosensing and early detection of diseases

     The Genome Engineering laboratory uses CRISPR/Cas9 technology to generate cellular models of human diseases. We apply the above technology extensively to study molecular origins of human cancers. In the past few years, we have successfully introduced targeted changes at the human genome to deplete/functionally inactivate cancer driver genes (breast, colorectal and childhood bone cancers). The sudden emergence of the COVID-19 pandemic and the demand for reliable diagnostic tools have directed our focus on innovations in applications of CRISPR tools in diagnostics. In less than five years, CRISPR-based diagnostics have evolved from a basic research tool to efficient clinically relevant diagnostic platforms. Currently, we aim at utilizing the existing opportunities to creating an improved workflow for generation of a portable, highly sensitive, rapid nucleic acid detection platform to aid: monitoring disease epidemiology, diagnostics and in laboratory tasks that require nucleic acid detection. Specifically, our long-term objective is to leverage the expertise of CRISPR within the genome engineering laboratory to create a nucleic-acid -base point-of-care (POC) diagnostic test for routine use in clinical care. Improvements made in this direction will be also utilised to facilitate monitoring genetic markers indicative of cancers which is one of the primary interests of our lab