The UVSSA protein is part of a genome integrity homeostasis network with links to transcription-coupled DNA repair and ATM signaling.
Magdalena M KordonSarah ArronJames E CleaverVladimir BezrookoveDeneb KarentzBrian LuEli PerrDarwin ChangThoru PedersonPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- dna repair
- dna damage
- crispr cas
- dna damage response
- transcription factor
- end stage renal disease
- protein protein
- amino acid
- regulatory t cells
- endothelial cells
- wild type
- induced apoptosis
- newly diagnosed
- binding protein
- magnetic resonance
- chronic kidney disease
- genome editing
- early onset
- patient reported outcomes
- mouse model
- dna methylation
- computed tomography
- cell death
- endoplasmic reticulum stress