Arresting transcription and sentencing the cell: The consequences of blocked transcription

• Polymerase is considered in broad view of mRNP assembly.
• An updated TC-NER model is presented.
• Arrested polymerases as processive DNA damage sensors are discussed.
• Therapeutic implications of targeting CS proteins are discussed.

Bulky DNA adducts induced by agents like ultraviolet light, cisplatin and oxidative metabolism pose a block to elongation by RNA polymerase II (RNAPII). The arrested RNAPII can initiate the repair of transcription-blocking DNA lesions by transcription-coupled nucleotide excision repair (TC-NER) to permit efficient recovery of mRNA synthesis while widespread sustained transcription blocks lead to apoptosis. Therefore, RNAPII serves as a processive DNA damage sensor that identifies transcription-blocking DNA lesions. Cockayne syndrome (CS) is an autosomal recessive disorder characterized by a complex phenotype that includes clinical photosensitivity, progressive neurological degeneration and premature-aging. CS is associated with defects in TC-NER and the recovery of mRNA synthesis, making CS cells exquisitely sensitive to a variety of DNA damaging agents. These defects in the coupling of repair and transcription appear to underlie some of the complex clinical features of CS. Recent insight into the consequences of blocked transcription and their relationship to CS will be discussed.