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Interference with transcription triggers a stress response leading to the induction of the tumour suppressor p53. If transcription is not restored within a certain time frame cells may undergo apoptosis in a p53-dependent and independent manner. The mechanisms by which blockage of transcription induces apoptosis may involve diminished levels of anti-apoptotic factors, inappropriate accumulation of proteins in the nucleus, accumulation of p53 at mitochondria or complications during replication. Many chemotherapeutic agents currently used in the clinic interfere with transcription and this interference may contribute to their anti-cancer activities. Future efforts should be directed towards exploring whether interference of transcription could be used as an anti-cancer therapeutic strategy.