Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation

Nat Struct Mol Biol. 2010 Apr;17(4):410-6. doi: 10.1038/nsmb.1773. Epub 2010 Mar 7.

Abstract

Chromosomal translocations in hematologic and mesenchymal tumors form overwhelmingly by nonhomologous end-joining (NHEJ). Canonical NHEJ, essential for the repair of radiation-induced and some programmed double-strand breaks (DSBs), requires the Xrcc4-ligase IV complex. For other DSBs, the requirement for Xrcc4-ligase IV is less stringent, suggesting the existence of alternative end-joining (alt-NHEJ) pathways. To understand the contributions of the canonical NHEJ and alt-NHEJ pathways, we examined translocation formation in cells deficient in Xrcc4-ligase IV. We found that Xrcc4-ligase IV is not required for but rather suppresses translocations. Translocation breakpoint junctions have similar characteristics in wild-type cells and cells deficient in Xrcc4-ligase IV, including an unchanged bias toward microhomology, unlike what is observed for intrachromosomal DSB repair. Complex insertions in some junctions show that joining can be iterative, encompassing successive processing steps before joining. Our results imply that alt-NHEJ is the primary mediator of translocation formation in mammalian cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Ligase ATP
  • DNA Ligases / metabolism*
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Translocation, Genetic*

Substances

  • DNA-Binding Proteins
  • XRCC4 protein, human
  • DNA Ligases
  • DNA Ligase ATP