Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer

Cell. 2009 Dec 11;139(6):1069-83. doi: 10.1016/j.cell.2009.11.030.


Chromosomal translocations are a hallmark of leukemia/lymphoma and also appear in solid tumors, but the underlying mechanism remains elusive. By establishing a cellular model that mimics the relative frequency of authentic translocation events without proliferation selection, we report mechanisms of nuclear receptor-dependent tumor translocations. Intronic binding of liganded androgen receptor (AR) first juxtaposes translocation loci by triggering intra- and interchromosomal interactions. AR then promotes site-specific DNA double-stranded breaks (DSBs) at translocation loci by recruiting two types of enzymatic activities induced by genotoxic stress and liganded AR, including activation-induced cytidine deaminase and the LINE-1 repeat-encoded ORF2 endonuclease. These enzymes synergistically generate site-selective DSBs at juxtaposed translocation loci that are ligated by nonhomologous end joining pathway for specific translocations. Our data suggest that the confluence of two parallel pathways initiated by liganded nuclear receptor and genotoxic stress underlies nonrandom tumor translocations, which may function in many types of tumors and pathological processes.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Introns
  • Long Interspersed Nucleotide Elements
  • Male
  • Open Reading Frames
  • Prostatic Neoplasms / genetics*
  • Receptors, Androgen / metabolism*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transcriptional Regulator ERG
  • Translocation, Genetic*


  • DNA-Binding Proteins
  • ERG protein, human
  • ETV1 protein, human
  • Receptors, Androgen
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Regulator ERG
  • Serine Endopeptidases
  • TMPRSS2 protein, human