Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target?

Abstract

An emerging model of transcriptional activation suggests that induction of transcriptional programs, for instance by stimulating prostate or breast cells with androgens or estrogens, respectively, involves the formation of DNA damage, including DNA double strand breaks (DSB), recruitment of DSB repair proteins, and movement of newly activated genes to transcription hubs. The DSB can be mediated by the class II topoisomerase TOP2B, which is recruited with the androgen receptor and estrogen receptor to regulatory sites on target genes and is apparently required for efficient transcriptional activation of these genes. These DSBs are recognized by the DNA repair machinery triggering the recruitment of repair proteins such as poly(ADP-ribose) polymerase 1 (PARP1), ATM, and DNA-dependent protein kinase (DNA-PK). If illegitimately repaired, such DSBs can seed the formation of genomic rearrangements like the TMPRSS2-ERG fusion oncogene in prostate cancer. Here, we hypothesize that these transcription-induced, TOP2B-mediated DSBs can also be exploited therapeutically and propose that, in hormone-dependent tumors like breast and prostate cancers, a hormone-cycling therapy, in combination with topoisomerase II poisons or inhibitors of the DNA repair components PARP1 and DNA-PK, could overwhelm cancer cells with transcription-associated DSBs. Such strategies may find particular utility in cancers, like prostate cancer, which show low proliferation rates, in which other chemotherapeutic strategies that target rapidly proliferating cells have had limited success.

Figure 1

An emerging model suggests that efficient induction of transcriptional programs can involve the generation of DNA double strand breaks and perhaps other DNA damage, repair of these breaks via recruitment of DNA repair proteins, and large scale movement of genes and regulatory elements to transcriptional hubs, in which transcription (co)factors are present at high local concentration. These events are illustrated for induction of transcriptional programs by AR. Upon transcriptional activation, AR associates with TOP2B and binds to AR target sites. DNA repair proteins including Ku70, Ku80, PARP1, ATM and DNA-PK and possibly other DNA repair enzymes also get recruited to these sites. TOP2B can mediate DSB in associated DNA. Reactive oxygen, perhaps generated during AR signaling, dietary carcinogens, and collision with the replication or transcription forks can transform these transient breaks into frank double strand breaks. Persistence of these breaks can result in induction of cellular senescence and apoptosis. Illegitimate repair of these breaks can lead to the formation of structural rearrangements. Such pathways are likely at work for other induced transcriptional programs, including those mediated by ER, RAR, and AP1.