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 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.
Lin
Chunru
C
Howard Hughes Medical Institute, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0648, USA.
Yang
Liuqing
L
Tanasa
Bogdan
B
Hutt
Kasey
K
Ju
Bong-gun
BG
Ohgi
Kenny
K
Zhang
Jie
J
Rose
David W
DW
Fu
Xiang-Dong
XD
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007438:Introns; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D016366:Open Reading Frames; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000071230:Transcriptional Regulator ERG; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; C072312:ERG protein, human; C095239:ETV1 protein, human; D011944:Receptors, Androgen; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human