title: Understanding and re-engineering nucleoprotein machines to cure human disease.
abstract: The mammalian nucleus is filled with self-organizing, nanometer-scale nucleoprotein machines that carry out DNA replication, RNA biogenesis and DNA repair. We discuss, as a model, the nonhomologous end-joining (NHEJ) machine, which repairs DNA double-strand breaks. The NHEJ machine consists of six core polypeptides and 10-20 ancillary polypeptides. A full understanding of its design principles will require measuring the behavior of single NHEJ complexes in living cells, using a Nano Toolbox that includes bright, stable, biocompatible fluorophores, efficient protein and nucleic acid-tagging strategies, and sensitive, high-resolution imaging methods. Taking inspiration from natural examples, it might be possible to adapt and redesign the NHEJ machine to precisely correct mutations responsible for common human diseases, such as K-ras in lung cancer or human papillomavirus E6 and E7 genes in cervical and oral cancers.
authors.affiliation: Institute of Molecular Medicine & Genetics, Medical College of Georgia, Augusta, GA 30912, USA. wdynan@mcg.edu
authors.forename: William
authors.initials: W
authors.lastname: Dynan
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Takeda
authors.forename: David
authors.initials: D
authors.lastname: Roth
authors.forename: Gang
authors.initials: G
authors.lastname: Bao
mesh_terms: D018390:Gene Targeting / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics* / Q000517:prevention & control*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008957:Models, Genetic; D009698:Nucleoproteins / Q000235:genetics*; D015202:Protein Engineering / Q000379:methods*
chemical_list: D009698:Nucleoproteins