Details

Autor(en) / Beteiligte

• Chaplin, Amanda K.
• Hardwick, Steven W.
• Stavridi, Antonia Kefala
• Buehl, Christopher J.
• Goff, Noah J.
• Ropars, Virginie
• Liang, Shikang
• De Oliveira, Taiana Maia
• Chirgadze, Dimitri Y.
• Meek, Katheryn
• Charbonnier, Jean-Baptiste
• Blundell, Tom L.

Titel

Cryo-EM of NHEJ supercomplexes provides insights into DNA repair

Ist Teil von

• Molecular cell, 2021-08, Vol.81 (16), p.3400-3409.e3

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Non-homologous end joining (NHEJ) is one of two critical mechanisms utilized in humans to repair DNA double-strand breaks (DSBs). Unrepaired or incorrect repair of DSBs can lead to apoptosis or cancer. NHEJ involves several proteins, including the Ku70/80 heterodimer, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray cross-complementing protein 4 (XRCC4), XRCC4-like factor (XLF), and ligase IV. These core proteins bind DSBs and ligate the damaged DNA ends. However, details of the structural assembly of these proteins remain unclear. Here, we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA, revealing the detailed structural architecture of this assembly. We describe monomeric and dimeric forms of this supercomplex and also propose the existence of alternate dimeric forms of long-range synaptic complexes. Finally, we show that mutational disruption of several structural features within these NHEJ complexes negatively affects DNA repair. [Display omitted] •Cryo-EM of NHEJ supercomplex structures consisting of DNA-PK, XLF, XRCC4, and LigIV•Description of two dimeric long-range synaptic complexes•Mutations in these dimeric NHEJ complexes negatively affect DNA repair•A model of NHEJ consisting of long- and short-range synaptic dimer complexes Non-homologous end joining (NHEJ) is a key mechanism that repairs DNA-double strand breaks. Using cryo-EM, Chaplin et al. present monomeric and dimeric structures of the core NHEJ proteins and reveal their structural architecture. Two long-range synaptic dimers are presented, and mutations of the dimer interfaces negatively affect DNA repair.