The dangers of transcription

Abstract

Transcription is obviously essential, but even a good thing can be dangerous at times. In this issue, Lin et al. (2009) provide evidence that binding of the transcription machinery may predispose genome regions to breakage and translocations that may lead to cancer.

Figure 1.. Pathways to Cancer Translocations

Translocations occur by breakage and illegitimate joining of distinct genomic regions (shown in orange and green) either within the same chromosome or on separate chromosomes. Multiple pathways contribute to the formation of translocations. In one pathway, androgen receptor (AR) binds to its target sites in the genome upon stimulation by androgen. Binding of AR induces local chromatin remodeling and leads to spatial association of multiple AR target sites, possibly making these regions susceptible to breakage. Upon genotoxic stress such as irradiation, AR recruits the activation-induced cytidine deaminase AID, which is capable of inducing DNA double-strand breaks. In a second pathway, ORF2, which is overex-pressed in cancer cells, associates with target sites in the genome in response to androgen signaling and induces double-strand breaks. Determinants of ORF2 expression and targeting are unknown. Juxtaposed chromosomes containing persistent double-strand breaks induced by either mechanism are prone to translocation. Such translocations may contribute to tumorigenesis.