Cryo-EM of NHEJ supercomplexes provides insights into DNA repair

• DOI: 10.1016/j.molcel.2021.07.005
• Publication Date: 2021-08-04T14:31:14Z
• Authors: Amanda K. Chaplin; Steven W. Hardwick; Antonia Kefala St...; Christopher J. Buehl; Noah J. Goff; Virginie Ropars; Shikang Liang; Taiana Maia De Ol...; Dimitri Y. Chirgadze; Katheryn Meek; Jean-Baptiste Cha...; Tom L. Blundell
• Keywords: 0301 basic medicine; 0303 health sciences; DNA End-Joining Repair; DNA Repair; Cryoelectron Microscopy; DNA repair; long-range synaptic complexes; Apoptosis; DNA-Activated Protein Kinase; Article; non-homologous end joining; DNA-PK; DNA-Binding Proteins; DNA Ligase ATP; 03 medical and health sciences; DNA Repair Enzymes; Multiprotein Complexes; cryo-EM; Humans; DNA Breaks, Double-Stranded; Phosphorylation; Ku Autoantigen; NHEJ; DNA Damage

Non-homologous end joining (NHEJ) is one of two critical mechanisms utilized in humans to repair DNA double-strand breaks (DSBs). Unrepaired or incorrect DSBs can lead apoptosis cancer. NHEJ involves several proteins, including the Ku70/80 heterodimer, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray cross-complementing 4 (XRCC4), XRCC4-like factor (XLF), and ligase IV. These core proteins bind ligate damaged ends. However, details structural assembly these remain unclear. Here, we present cryo-EM structures supercomplexes that are composed DNA, revealing detailed architecture this assembly. We describe monomeric dimeric forms supercomplex also propose existence alternate long-range synaptic complexes. Finally, show mutational disruption features within complexes negatively affects repair.