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

By Chunru Lin, Liuqing Yang, Bogdan Tanasa, Kasey R. Hutt, B. Ju, Kenny Ohgi, Jie Zhang, David W. Rose, Xiang-Dong Fu, Christopher K. Glass and 1 more. Cell, 2009

609 citations recorded by the source corpus.

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-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 machinery induced by genotoxic stress and liganded-AR, including Activation-Induced Cytidine Deaminase (AID) and the LINE-1 repeat-encoded ORF2 endonuclease. These enzymatic machineries synergistically generate site-selective DSBs at juxtaposed translocation loci that are ligated by Non-Homologous Ending Joining (NHEJ) pathway for specific translocations. Our data suggest that the confluence of two parallel pathways initiated by liganded-nuclear receptor and genotoxic stress underlie non-random tumor translocations, which may function in many types of tumors and pathological processes.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f27f2f74a10a5866ebc40c057785a802c29b8ec8

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Citations in the corpus

Punctuated Evolution of Prostate Cancer Genomes (2013, neutral): “Our analysis of breakpoint locations in ETS tumors suggests that chromoplexy in this setting may be linked to proposed transcriptional DNA-damaging processes (Lin et al., 2009), potentially related to androgen receptor signaling.”
Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “…may be an indirect consequence of AR function, as studies in androgen-responsive LNCaP cells have shown that AR binding induces chromosomal proximity between the TMPRSS2 and ERG loci that can lead to formation of TMPRSS2-ERG fusions following DNA damage (Lin et al. 2009; Mani et al. 2009).”
Androgen-induced TOP2B mediated double strand breaks and prostate cancer gene rearrangements (2010, background): “Another report has suggested that in the presence of high levels of exogenous genotoxic stress, other enzymes such as activation-induced cytidine deaminase (AID) and LINE-1 repeat-encoded ORF2 endonuclease can cooperate with androgen receptor signaling to establish DSBs and, ultimately, prostate can”
An ATM-Dependent Transcriptional Silencing Program is Transmitted Through Chromatin in Cis to DNA Double Strand Breaks (2010, background): “Indeed, transcriptional activation by androgen receptor has recently been reported to promote translocations between target genes on noncontiguous chromosomal sites (Lin et al., 2009) .”
The genomic complexity of primary human prostate cancer (2011, positive): “In prostate cells, androgen signaling has been shown to induce co-localization of TMPRSS2 and ERG , thereby allowing double-strand breaks to facilitate gene fusion formation 31 – 33 .”
Biogenesis and Function of Nuclear Bodies (2011, background): “DSBs are later ligated by non-homologous end joining (NHEJ) to create non-random chromosomal translocations in prostate tumors [86].”