Cryo-EM structure of a DNA-PK trimer: higher order oligomerisation in NHEJ

Structure. 2023 Aug 3;31(8):895-902.e3. doi: 10.1016/j.str.2023.05.013. Epub 2023 Jun 12.

Abstract

The ability of humans to maintain the integrity of the genome is imperative for cellular survival. DNA double-strand breaks (DSBs) are considered the most critical type of DNA lesion, which can ultimately lead to diseases including cancer. Non-homologous end joining (NHEJ) is one of two core mechanisms utilized to repair DSBs. DNA-PK is a key component in this process and has recently been shown to form alternate long-range synaptic dimers. This has led to the proposal that these complexes can be formed before transitioning to a short-range synaptic complex. Here we present cryo-EM data representing an NHEJ supercomplex consisting of a trimer of DNA-PK in complex with XLF, XRCC4, and DNA Ligase IV. This trimer represents a complex of both long-range synaptic dimers. We discuss the potential role of the trimeric structure, and possible higher order oligomers, as structural intermediates in the NHEJ mechanism, or as functional DNA repair centers.

Keywords: DNA repair; DNA-PK trimer; NHEJ; cryo-EM; oligomerisation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • DNA / genetics
  • DNA End-Joining Repair
  • DNA Ligase ATP
  • DNA Repair Enzymes* / genetics
  • DNA Repair Enzymes* / metabolism
  • DNA Repair*
  • DNA-Activated Protein Kinase / metabolism
  • Humans

Substances

  • DNA Repair Enzymes
  • DNA Ligase ATP
  • DNA-Activated Protein Kinase
  • DNA