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 THUWAL,  Kingdom of Saudi Arabia,  June 11, 2013  /PRNewswire/ --King Abdullah University of Science and Technology (KAUST) Assistant Professorof Chemistry and Biology and Principal Investigator of the Laboratory of DNAReplication and Recombination, Dr.  Samir M. Hamdan, and his team, havepublished a groundbreaking paper on the mechanism of flap endonuclease 1 (FEN1),in  Cell Reports  journal. The other authors of the paper, entitled "Sequentialand Multistep Substrate Interrogation Provides the Scaffold for Specificity inHuman Flap Endonuclease 1," are:  Mohamed A. Sobhy,  Luay I. Joudeh,  XiaojuanHuang, and  Masateru Takahashi.     (Logo:  
  http://photos.prnewswire.com/prnh/20130611/619032
   )5' nucleases, the superfamily to which FEN1 belongs,represent structure-specificnucleases essential for DNA replication, repair, and recombination. Deficienciesin their genes have been linked to several types of cellular stress and genomicinstability.Their outstanding puzzle is that they are highly conserved proteins,yet they recognize a diverse range of RNA and DNA structures and cleave themprimarily at the same position relative to a 5' end of a junction.Structural studies propose a solution for this geometrical puzzle by capturing aDNA bending intermediary step that position the 5' end in the enzyme activepocket and unify the 5' nucleases cleavage site. However, these structuresremain a static image of the DNA bending intermediary step based on whichspeculation was made to address the most important questions regarding how thisintermediary step is induced and how 5' nucleases utilize the same intermediarystep to recognize diverse range of substrates.The team from KAUST's Division of Biological and Environmental Sciences andEngineering employed a sophisticated single molecule imaging technique, F?rsterresonance energy transfer (smFRET), to capture "molecular movies" detailing thestructure, dynamics, and reaction mechanisms occurring during this process. TheKAUST scientists were able to build a timeline of up to seven intermediary stepsbefore FEN1 commits to catalysis. Such information cannot be accessed throughconventional approaches.These findings will influence how researchers think about the mechanism of othermembers of 5' nucleases and provide a new concept as to how biologicalmacromolecules can diversify their substrate specificity while maintaining ahigh degree of structural similarities.Dr. Hamdan explained that the surprising finding is that FEN1 utilizes a highlycomplex mechanism that sequentially verifies all substrate features beforeinducing the superfamily unifying DNA bending intermediary. This sequential andmultistep substrate recognition process provides a scaffold that allowsdifferent 5' nucleases to recognize different substrates and restrict theinduction of DNA bending to the last common step. "We hope that our findingswill serve as a base to design inhibitors against FEN1, whose expression ishighly correlated with tumor aggressiveness," said Prof. Hamdan.Links:  * "Sequential and Multistep Substrate Interrogation Provides the Scaffold forSpecificity in Human Flap Endonuclease 1" Cell Reports  online* "A Scientific Oasis in a Desert" Cell Reporter  blog post by Dr. Hamdan* KAUST website  About KAUSTKing Abdullah University of Science and Technology (KAUST) is an international,graduate research university dedicated to advancing science and technologythrough interdisciplinary research, education, and innovation. Students,faculty, scientists, and engineers conduct fundamental and goal-orientedresearch to address the world's pressing scientific and technological challengesrelated to water, food, energy, and the environment.Located on the shores of the Red Sea, KAUST is the first LEED certified projectin  Saudi Arabia  and the largest LEED Platinum project in the world. In 2011,KAUST was named Lab of the Year by leading science and technology publication, R&D Magazine.The following year, the University's Research Park was named the2012 Emerging Research and Science Park by the Association of UniversityResearch Parks (AURP).  
  http://www.kaust.edu.sa
 Samia Falimban, Head of University Communications,  samia.falimban@kaust.edu.sa,Telephone: +966(0)2-808-3242SOURCE  King Abdullah University of Science and Technology