Poster Presentation The 46th Lorne Conference on Protein Structure and Function 2021

strumNHEJ - A structural database of mutations in NHEJ repair leading to cancer and their molecular consequences (#116)

Raghad Al Jarf 1 2 3 , YooChan Myung 1 2 3 , Azadeh Alavi 3 , Malancha Karmakar 1 2 3 , Stephanie Portelli 1 2 3 , Douglas E.V. Pires 1 2 3 4 , David B. Ascher 1 2 3 5
  1. University of Melbourne, Parkville, VIC, Australia
  2. Structural Biology and Bioinformatics, Department of Biochemistry, The Bio21 Molecular Science and Biotechnology Institute University of Melbourne, Melbourne, Victoria, Australia
  3. Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
  4. Systems and Computational Biology, Bio21 Institute, University of Melbourne, 30 Flemington Rd, Parkville VIC 3052
  5. Department of Biochemistry, University of Cambridge, 80 Tennis Ct Rd, Cambridge CB2 1GA

Abstract:                   

Mutations in non-homologous end joining (NHEJ) DNA repair genes are associated with a range of human syndromes including microcephaly, growth delay, Fanconi anemia, as well as different hereditary cancers. Very little has been done previously to systematically record NHEJ variants associated with cancers and cancer risk, however these are either incomplete or outdated. To fill this gap, we have developed a comprehensive catalogue of NHEJ variants from genes known to be mutated in cancer, providing a resource for better understanding their role and molecular mechanisms in disease from a structural perspective. Over 1,131 cancer associated variants and 1,852 population variants were mapped to the principal components of the NHEJ system- DNA-Lig IV, DNA-PKcs, Ku70/80 and XRCC4. All cancer associated and population variants were mapped to experimental structures, capturing some of the intricate series of interactions between the NHEJ components. These can be easily visualised and inspected through a user-friendly web interface to rapidly assess their spatial distribution within the protein domains, protein structures and protein-protein complexes. The molecular and structural consequences of the variants were evaluated using the mCSM platform to quantitatively assess their impact on protein folding, dynamics, stability, and interactions. This revealed that cancer driving variants in anchor proteins, such as Ku70/80, were more likely to affect key protein-protein interactions, whilst those in the enzymatic components, such as DNA-PKcs, were more likely to be found in intolerant regions undergoing purifying selection. Using this insight, we built a consensus predictor that was able to accurately identify driving mutations, up to 80% accuracy (and 0.78 AUC).We believe that strumNHEJ will be a powerful resource to better understand the role of non-homologous end joining DNA repair in genetic disorders. strumNHEJ is freely available at http://biosig.unimelb.edu.au/strumnhej.