Transcription-Coupled DNA Repair: From Mechanism to Human Disorder. Issue 5 (May 2021) - van den Heuvel, Diana
Abstract : DNA lesions pose a major obstacle during gene transcription by RNA polymerase II (RNAPII) enzymes. The transcription-coupled DNA repair (TCR) pathway eliminates such DNA lesions. Inherited defects in TCR cause severe clinical syndromes, including Cockayne syndrome (CS). The molecular mechanism of TCR and the molecular origin of CS have long remained enigmatic. Here we explore new advances in our understanding of how TCR complexes assemble through cooperative interactions between repair factors stimulated by RNAPII ubiquitylation. Mounting evidence suggests that RNAPII ubiquitylation activates TCR complex assembly during repair and, in parallel, promotes processing and degradation of RNAPII to prevent prolonged stalling. The fate of stalled RNAPII is therefore emerging as a crucial link between TCR and associated human diseases. Highlights: Recent advances in methods to isolate TCR complexes revealed a sequential and cooperative assembly of CSB, CSA, and UVSSA onto DNA damage-stalled RNAPII. The UV-induced ubiquitylation of a single lysine residue in the largest subunit of RNAPII (RPB1-K1268) by CRL4 E3 ligases, including CRL4 CSA, is a key regulator of TCR and, together with the ubiquitylation of UVSSA (K414), promotes the transfer of TFIIH onto RNAPII to initiate DNA repair. The CS protein-dependent ubiquitylation of RPB1-K1268 acts as a molecular clock that promotes DNA repair at early time-points, but leads to the removal of DNA damage-stalled RNAPII when repair fails. Rather than a DNA repair disorder, emerging evidence suggests that Cockayne syndrome is caused by a deficiency in processing RNAPII, resulting in its prolonged arrest at DNA lesions, ultimately causing neurodegeneration.