Androgen-induced TOP2B mediated double strand breaks and prostate cancer gene rearrangements

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Abstract

DNA double strand breaks (DSB) can lead to development of genomic rearrangements, which are hallmarks of cancer. TMPRSS2-ERG gene fusions in prostate cancer (PCa) are among the most common genomic rearrangements observed in human cancer. We show that androgen signaling promotes co-recruitment of androgen receptor (AR) and topoisomerase II beta (TOP2B) to sites of TMPRSS2-ERG genomic breakpoints, triggering recombinogenic TOP2B-mediated DSB. Furthermore, androgen stimulation resulted in de novo production of TMPRSS2-ERG fusion transcripts in a process requiring TOP2B and components of DSB repair machinery. Finally, unlike normal prostate epithelium, prostatic intraepithelial neoplasia (PIN) cells showed strong co-expression of AR and TOP2B. These findings implicate androgen-induced TOP2B-mediated DSB in generating TMPRSS2-ERG rearrangements.

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DNA double-strand breaks (DSBs) are extremely dangerous lesions with severe consequences for cell survival and the maintenance of genomic stability. In higher eukaryotic cells, DSBs in chromatin promptly initiate the phosphorylation of the histone H2A variant, H2AX, at Serine 139 to generate γ-H2AX. This phosphorylation event requires the activation of the phosphatidylinositol-3-OH-kinase-like family of protein kinases, DNA-PKcs, ATM, and ATR, and serves as a landing pad for the accumulation and retention of the central components of the signaling cascade initiated by DNA damage. Regions in chromatin with γ-H2AX are conveniently detected by immunofluorescence microscopy and serve as beacons of DSBs. This has allowed the development of an assay that has proved particularly useful in the molecular analysis of the processing of DSBs. Here, we first review the role of γ-H2AX in DNA damage response in the context of chromatin and discuss subsequently the use of this modification as a surrogate marker for mechanistic studies of DSB induction and processing. We conclude with a critical analysis of the strengths and weaknesses of the approach and present some interesting applications of the resulting methodology.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 4 August 2011

Publication date (Electronic): 04 July 2010

Publication date (Print): August 2010

Publication date PMC-release: 17 August 2011

Volume: 42

Issue: 8

Pages: 668-675

Affiliations

[1 ]Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, Maryland, 21231 USA

[2 ]Department of Biostatistics, Bloomberg School of Public Health, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, Maryland, 21231 USA

[3 ]Department of Pathology, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, Maryland, 21231 USA

[4 ]Brady Urological Institute, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, Maryland, 21231 USA

[5 ]Center for Cancer Genomics, Wake Forrest University Health Sciences, Medical Center Boulevard, Wake Forrest, North Carolina, 27157 USA

Author notes

Correspondence and requests for materials should be addressed to S.Y. ( syegnasu@ 123456jhmi.edu ) or W.G.N. ( bnelson@ 123456jhmi.edu )

[*]

These authors contributed equally to this work.

Article

Manuscript ID: nihpa210961

DOI: 10.1038/ng.613

PMC ID: 3157086

PubMed ID: 20601956

SO-VID: 26d6eb7e-2b26-4d65-a559-b2b5b8363c2a

License:

Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

History

Funding

Funded by: National Cancer Institute : NCI

Award ID: R01 CA070196-13 || CA

Funded by: National Cancer Institute : NCI

Award ID: P50 CA058236-16 || CA

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