​Date: Wednesday, December 21st, 2016 

Time: 11:00 AM 

Location: Building 4, Room 125

Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology.  KSA

 

Structure-specific 5'-nucleases recognize a diverse range of aberrant DNA structures: nicks, gaps, flaps, bubble and four-way junctions. These pathway intermediates are highly common in DNA replication, recombination and repair but also are toxic underscoring the human diseases associated with their mutations. Recent structural and biochemical analysis have revealed potential mechanisms of DNA bending and deliberate unpairing, but these mechanisms remain controversial and their contribution to substrate specificity is largely unknown. Here I will present single molecule Förster resonance energy transfer study on the superfamily member human flap endonuclease-1 (FEN1) showing that coupling conformational changes on both FEN1 and substrate with active site assembly controls its catalytic selectivity. This coupling is mutual when encountering cognate substrate and stabilizes a transition state that has been thoroughly vetted by multiple checks and cleaves without missed opportunity. While noncognate substrates disrupt this coupling and drastically reduced its probability to assemble a catalytically competent active site. These results provide the first example of how catalytic selectivity is achieved in structure specific nucleases without relying on a specific DNA sequence or even non-conical nucleotide.

 

Prof Hamdan finished his PhD from Australian National University (Canberra) and did his postdoctoral studies at Harvard Medical School. In 2009, he started his academic career as an Assistant Professor at King Abdullah University of Science Technology and is currently an Associate Professor of Biosciences. His research interest focuses on understanding the molecular mechanisms involved in DNA replication and its interplay with other process such as repair and recombination. By combining biochemical, biophysical, and structural tools with the real time observation of single-molecule imaging techniques he aims to advance our understanding of the molecular mechanisms underlying these processes.

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