Nuclear Receptor-Induced Chromosomal Proximity and DNA Breaks Underlie Specific Translocations in Cancer

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...

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Bibliographic Details
Published in:Cell 2009-12, Vol.139 (6), p.1069-1083
Main Authors: Lin, Chunru, Yang, Liuqing, Tanasa, Bogdan, Hutt, Kasey, Ju, Bong-gun, Ohgi, Kenneth A., Zhang, Jie, Rose, David W., Fu, Xiang-Dong, Glass, Christopher K., Rosenfeld, Michael G.
Format: Article
Language:English
Subjects:
Activation-induced cytidine deaminase
Androgen receptors
Cancer
Cell Line, Tumor
Chromosome translocations
Data processing
DNA
DNA Damage
DNA Repair
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endonuclease
Enzymatic activity
Genotoxicity
Humans
HUMDISEASE
Introns
Leukemia
Long Interspersed Nucleotide Elements
Lymphoma
Male
Nuclear receptors
Nuclear transport
Open Reading Frames
Prostatic Neoplasms - genetics
Receptors, Androgen - metabolism
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
SIGNALING
Solid tumors
Trans-Activators - genetics
Trans-Activators - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
Transcriptional Regulator ERG
Translocation, Genetic
Tumors
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Description
Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2009.11.030