General transcription is required for the growth and survival of all living cells. However, tumor cells require extraordinary levels of transcription, including the transcription of ribosomal RNA genes by RNA polymerase I (RNPI) and mRNA by RNA polymerase II (RNPII). In fact, cancer cells have mutations that directly enhance transcription and are frequently required for cancer transformation. For example, the recent discovery that MYC enhances the transcription of the majority genes in the genome correlates with the fact that several transcription interfering drugs preferentially kill cancer cells. In recent years, advances in the mechanistic studies of the basal transcription machinery and the discovery of drugs that interfere with multiple components of transcription are being used to combat cancer. For example, drugs such as triptolide that targets the general transcription factors TFIIH and JQ1 to inhibit BRD4 are administered to target the high proliferative rate of cancer cells. Given the importance of finding new strategies to preferentially sensitize tumor cells, this review primarily focuses on several transcription inhibitory drugs to demonstrate that the basal transcription machinery constitutes a potential target for the design of novel cancer drugs. We highlight the drugs’ mechanisms for interfering with tumor cell survival, their importance in cancer treatment and the challenges of clinical application.

Background: TFIIH interacts with multiple factors. Results: The fly p8 subunit of TFIIH is encoded in a bicistronic transcript with the homolog of the Swc6/p18Hamlet subunit of the SWR1/SRCAP complex and physically and genetically interacts with TFIIH. Conclusion: There is a functional link between Swc6/p18Hamlet and TFIIH. Significance: This functional interaction opens new avenues to study how TFIIH modulates transcription and DNA repair.

SummaryTranscription factor IIH (TFIIH) participates in transcription, nucleotide excision repair and the control of the cell cycle. In the present study, we demonstrate that the Dmp52 subunit of TFIIH in Drosophila physically interacts with the fly p53 homologue, Dp53. The depletion of Dmp52 in the wing disc generates chromosome fragility, increases apoptosis and produces wings with a reduced number of cells; cellular proliferation, however, is not affected. Interestingly, instead of suppressing the apoptotic phenotype, the depletion of Dp53 in Dmp52-depleted wing disc cells increases apoptosis and the number of cells that suffer from chromosome fragility. The apoptosis induced by the depletion of Dmp52 alone is partially dependent on the JNK pathway. In contrast, the enhanced apoptosis caused by the simultaneous depletion of Dp53 and Dmp52 is absolutely JNK-dependent. In this study, we also show that the anti-proliferative drug triptolide, which inhibits the ATPase activity of the XPB subunit of TFIIH, phenocopies the JNK-dependent massive apoptotic phenotype of Dp53-depleted wing disc cells; this observation suggests that the mechanism by which triptolide induces apoptosis in p53-deficient cancer cells involves the activation of the JNK death pathway.