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XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair

Academic Article
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Overview

authors

  • Mahaney, B. L.
  • Hammel, M.
  • Meek, K.
  • Tainer, John
  • Lees-Miller, S. P.

publication date

  • February 2013

journal

  • Biochemistry and Cell Biology-Biochimie Et Biologie Cellulaire  Journal

abstract

  • DNA double strand breaks (DSBs), induced by ionizing radiation (IR) and endogenous stress including replication failure, are the most cytotoxic form of DNA damage. In human cells, most IR-induced DSBs are repaired by the nonhomologous end joining (NHEJ) pathway. One of the most critical steps in NHEJ is ligation of DNA ends by DNA ligase IV (LIG4), which interacts with, and is stabilized by, the scaffolding protein X-ray cross-complementing gene 4 (XRCC4). XRCC4 also interacts with XRCC4-like factor (XLF, also called Cernunnos); yet, XLF has been one of the least mechanistically understood proteins and precisely how XLF functions in NHEJ has been enigmatic. Here, we examine current combined structural and mutational findings that uncover integrated functions of XRCC4 and XLF and reveal their interactions to form long, helical protein filaments suitable to protect and align DSB ends. XLF-XRCC4 provides a global structural scaffold for ligating DSBs without requiring long DNA ends, thus ensuring accurate and efficient ligation and repair. The assembly of these XRCC4-XLF filaments, providing both DNA end protection and alignment, may commit cells to NHEJ with general biological implications for NHEJ and DSB repair processes and their links to cancer predispositions and interventions.

subject areas

  • Cell Transformation, Neoplastic
  • DNA
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair
  • DNA Ligases
  • DNA Repair
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Humans
  • Models, Molecular
  • Protein Binding
  • Radiation, Ionizing
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Research

keywords

  • DNA double strand break
  • DNA repair
  • XLF
  • XRCC4
  • nonhomologous end joining
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Identity

PubMed Central ID

  • PMC3725335

International Standard Serial Number (ISSN)

  • 0829-8211

Digital Object Identifier (DOI)

  • 10.1139/bcb-2012-0058

PubMed ID

  • 23442139
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Additional Document Info

start page

  • 31

end page

  • 41

volume

  • 91

issue

  • 1

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