Increased global transcription activity as a mechanism of replication stress in cancer

Abstract

Cancer is a disease associated with genomic instability that often results from oncogene activation. This in turn leads to hyperproliferation and replication stress. However, the molecular mechanisms that underlie oncogene-induced replication stress are still poorly understood. Oncogenes such as HRASV12 promote proliferation by upregulating general transcription factors to stimulate RNA synthesis. Here we investigate whether this increase in transcription underlies oncogene-induced replication stress. We show that in cells overexpressing HRASV12, elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which together with R-loop accumulation results in replication fork slowing and DNA damage. Furthermore, overexpression of TBP alone causes the hallmarks of oncogene-induced replication stress, including replication fork slowing, DNA damage and senescence. Consequently, we reveal that increased transcription can be a mechanism of oncogene-induced DNA damage, providing a molecular link between upregulation of the transcription machinery and genomic instability in cancer.

Fragile sites in cancer: more than meets the eye

“…Similarly, Cyclin E deregulation causes cells to enter mitosis with incompletely replicated regions, including CFSs and late replicating domains 118 . Interestingly, oncogene stimulation of transcription and associated R-loop formation, where RNA hybridizes to a complementary DNA strand, forming an RNA/DNA hybrid with displacement of the other DNA strand, is one important mechanism by which these replication outcomes arise, further supporting a link between transcription, replication and genomic instability in cancer 119 .…”

Regulation of DNA Replication through Natural Impediments in the Eukaryotic Genome

“…Both processes are carried out by large protein complexes that move processively along the genome and cause temporary but significant alterations to the DNA structure. Collisions between the transcription and replication machineries are a clear source of genomic instability in both prokaryotes and eukaryotes [187,188,189], and have recently been linked to oncogene-induced DNA damage in cancer cells [190]. In this section, we attempt to summarize the current knowledge on the molecular basis of transcription–replication encounters and the consequences of their dysregulation.…”

The Role of the Transcriptional Response to DNA Replication Stress

“…This misregulation of the replication programme is thought to result in increased replication and transcription collisions, resulting in replication stress [47]. Overexpression of another oncogene, HRAS V12 , instead increases transcription levels to increase the frequency of collisions and cause replication stress [48]. …”