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Published on: March 31, 2022
Transcription-Coupled DNA Repair: From Mechanism to Human Disorder
Diana van den Heuvel1, Yana van der Weegen1, Daphne E C Boer1
1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
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.
Insights
DNA repair pathways fix DNA lesions that block transcription. New research shows RNA polymerase II ubiquitylation triggers repair complex assembly and RNAPII degradation, linking transcription-coupled repair to diseases like Cockayne syndrome.
Area of Science:
- Molecular biology
- Genetics
- Biochemistry
Background:
- DNA lesions impede gene transcription by RNA polymerase II (RNAPII).
- The transcription-coupled DNA repair (TCR) pathway resolves these lesions.
- Defects in TCR are linked to severe inherited disorders like Cockayne syndrome (CS).
Purpose of the Study:
- To elucidate the molecular mechanisms of TCR complex assembly.
- To understand the role of RNAPII ubiquitylation in TCR.
- To clarify the molecular origins of Cockayne syndrome.
Main Methods:
- Investigating the cooperative interactions between TCR factors.
- Analyzing the impact of RNAPII ubiquitylation on TCR complex formation.
- Examining RNAPII processing and degradation during stalled transcription.
Main Results:
- RNAPII ubiquitylation is a key activator of TCR complex assembly.
- Ubiquitylation promotes the processing and degradation of stalled RNAPII.
- This prevents prolonged transcription stalling and links TCR to human diseases.
Conclusions:
- RNAPII ubiquitylation orchestrates TCR complex assembly and RNAPII turnover.
- The fate of stalled RNAPII is a critical determinant in TCR and associated diseases.
- This provides new insights into the molecular basis of Cockayne syndrome.
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