Distinct Pathways of Nonhomologous End Joining that Are Differentially Regulated by DNA-dependent Protein Kinase-mediated Phosphorylation

Durga Udayakumar, Catherine L. Bladen, Farlyn Z. Hudson, William S. Dynan

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Nonhomologous end joining is the most common mechanism of DNA double-strand break repair in human cells. Here we show that nonhomologous end joining can occur by two biochemically distinct pathways. One requires a fraction containing the Mre11-Rad50-NBS1 complex. The other requires a fraction containing a novel, ∼200-kDa factor that does not correspond to any of the previously described double-strand break repair proteins. The two pathways converge, sharing a common requirement for the DNA ligase IV-XRCC4 complex to catalyze the final step of phosphodiester bond formation. Whereas the Mre11-Rad50-NBS1-dependent pathway does not require, and may be inhibited by, DNA-dependent protein kinase-mediated phosphorylation, the new pathway depends on this phosphorylation for release from a DNA-dependent protein kinase-mediated reaction checkpoint. The existence of two distinct pathways, which are differentially regulated by the DNA-dependent protein kinase, provides a possible explanation for the selective repair defects seen in DNA-dependent protein kinase-deficient mutants.

Original languageEnglish (US)
Pages (from-to)41631-41635
Number of pages5
JournalJournal of Biological Chemistry
Volume278
Issue number43
DOIs
StatePublished - Oct 24 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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