2. Academic Validation
  3. FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4

FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4

  • Mol Cell. 2016 Feb 4;61(3):419-433. doi: 10.1016/j.molcel.2015.12.010.
Qiang Zhang 1,  David Karnak 1,  Mingjia Tan 1,  Theodore S Lawrence 1,  Meredith A Morgan 2,  Yi Sun 3
Affiliations

Affiliations

  • 1 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
  • 3 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, Zhejiang, China. Electronic address: [email protected].
PMID: 26774286 DOI: 10.1016/j.molcel.2015.12.010
Abstract

FBXW7 is a haploinsufficient tumor suppressor with loss-of-function mutations occurring in human cancers. FBXW7 inactivation causes genomic instability, but the mechanism remains elusive. Here we show that FBXW7 facilitates nonhomologous end-joining (NHEJ) repair and that FBXW7 depletion causes radiosensitization. In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair. Consistent with these findings, a small-molecule inhibitor that abrogates XRCC4 polyubiquitylation reduces NHEJ repair. Our study demonstrates one mechanism by which FBXW7 contributes to genome integrity and implies that inactivated FBXW7 in human cancers could be a strategy for increasing the efficacy of radiotherapy.

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