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Title | The small CRL4 ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 6374, Year 2024 |
Publish date | Jul 29, 2024 |
Authors | Diana A Llerena Schiffmacher / Shun-Hsiao Lee / Katarzyna W Kliza / Arjan F Theil / Masaki Akita / Angela Helfricht / Karel Bezstarosti / Camila Gonzalo-Hansen / Haico van Attikum / Matty Verlaan-de Vries / Alfred C O Vertegaal / Jan H J Hoeijmakers / Jurgen A Marteijn / Hannes Lans / Jeroen A A Demmers / Michiel Vermeulen / Titia K Sixma / Tomoo Ogi / Wim Vermeulen / Alex Pines / |
PubMed Abstract | Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional ...Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4). Although ubiquitination of several TC-NER proteins by CRL4 has been reported, it is still unknown how this complex is regulated. To unravel the dynamic molecular interactions and the regulation of this complex, we apply a single-step protein-complex isolation coupled to mass spectrometry analysis and identified DDA1 as a CSA interacting protein. Cryo-EM analysis shows that DDA1 is an integral component of the CRL4 complex. Functional analysis reveals that DDA1 coordinates ubiquitination dynamics during TC-NER and is required for efficient turnover and progression of this process. |
External links | Nat Commun / PubMed:39075067 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.4 - 6.98 Å |
Structure data | EMDB-18377: Focused map for CSA-DDB1-DDA1 EMDB-18378: Focused map for CSA-DDB1-DDA1 (map 2) EMDB-18380: Focused map for UVSSA(VHS)-CSA-DDB1(BPA/BPC)-DDA1 EMDB-18413: Consensus map of UVSSA(VHS)-CSA-DDB1-DDA1 |
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