SignificanceTranscription-coupled repair (TCR) involves four core proteins: CSA, CSB, USP7, and UVSSA. CSA and CSB are mutated in the severe human neurocutaneous disease Cockayne syndrome. In contrast UVSSA is a mild photosensitive disease in which a mutated protein sequence prevents recruitment of USP7 protease to deubiquitinate and stabilize CSB. We deleted the UVSSA protein using CRISPR-Cas9 in an aneuploid cell line, HEK293, and determined the functional consequences. The knockout cell line was sensitive to transcription-blocking lesions but not sensitive to oxidative agents or PARP inhibitors, unlike CSB. Knockout of UVSSA also activated ATM, like CSB, in transcription-arrested cells. The phenotype of UVSSA, especially its rarity, suggests that many TCR-deficient patients and tumors fail to be recognized clinically.
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| http://dx.doi.org/10.1073/pnas.2116254119 | DOI Listing |
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Transcription-coupled repair - mechanisms of action, regulation, and associated human disorders.
FEBS Lett
December 2024
Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
The transcription-coupled repair (TCR) pathway resolves transcription-blocking DNA lesions to maintain cellular function and prevent transcriptional arrest. Stalled RNA polymerase II (RNAPII) triggers repair mechanisms, including RNAPII ubiquitination, which recruit UVSSA and TFIIH. Defects in TCR-associated genes cause disorders like Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and recently defined AMeDS.
View Article and Find Full Text PDFSTK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair.
Cell
December 2024
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:
Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear.
View Article and Find Full Text PDFSTK19 positions TFIIH for cell-free transcription-coupled DNA repair.
Cell
December 2024
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA, USA. Electronic address:
In transcription-coupled nucleotide excision repair (TC-NER), stalled RNA polymerase II (RNA Pol II) binds CSB and CRL4, which cooperate with UVSSA and ELOF1 to recruit TFIIH. To explore the mechanism of TC-NER, we recapitulated this reaction in vitro. When a plasmid containing a site-specific lesion is transcribed in frog egg extract, error-free repair is observed that depends on CSB, CRL4, UVSSA, and ELOF1.
View Article and Find Full Text PDFSTK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment.
Mol Cell
December 2024
Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands. Electronic address:
Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II). TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which recruits the CRL4 ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4 serves as a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment.
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DNA Repair (Amst)
November 2024
Institute for Cancer Genetics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA; Department of Genetics and Development, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA. Electronic address:
DNA interstrand crosslinks (ICLs) are covalent bonds between bases on opposing strands of the DNA helix which prevent DNA melting and subsequent DNA replication or RNA transcription. Here, we show that Ultraviolet Stimulated Scaffold Protein A (UVSSA) is critical for ICL repair in human cells, at least in part via the transcription coupled ICL repair (TC-ICR) pathway. Inactivation of UVSSA sensitizes human cells to ICL-inducing drugs, and delays ICL repair.
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