Nucleotide Excision Repair controls RNA polymerase II levels

JUAN CRISTOBAL MUÑOZ; INES BECKERMAN; RAMVEER CHOUDHARY; LEON ALBERTO BOUVIER; MARCO FOIANI; MANUEL J. MUÑOZ

Ottawa

Congreso; 13th International Conference on Environmental Mutagens Maintaining Genomic Health in a Changing World, 53rd Annual Meeting of the EMGS. August 27th - September 1st, 2022, Ottawa, Canada; 2022

EMGS

RPB1, the major and catalytic subunit of human RNA Polymerase II (RNAPII), is specifically degraded by theubiquitin-proteasome system upon UV-induced DNA damage. Current RNAPII degradation models exclusivelyrely on in cis degradation, where a stalled RNAPII functions as a lesion recognition factor that is later degradedin order to facilitate access to core Nucleotide Excision Repair (NER) factors. This Transcription Coupled -NER(TC-NER) system is complemented by the Global Genome -NER (GG-NER), which recognizes lesions throughXPE and XPC and shares with TC-NER the core NER factors involved in the actual repair. Here we show that in asecond phase after UV irradiation, and when TC-NER is no longer active, RNAPII degradation is prevented incells lacking XPE and XPC and, therefore, triggered in trans by GG-NER. Accordingly with an in transmechanism, UV-induced RNAPII degradation is not restricted to phosphorylated or chromatin bound RNAPIImolecules. Finally, and further strengthening the role of NER in the control of RNAPII levels, incomplete lesionrepair due to absence of any core NER factor induce an enhancement in RNAPII degradation, demonstratingthat the signaling for RNAPII degradation is started by lesion recognition, either by TC- or GG-NER, and endsafter the repair process is complete. These findings provide a rationale for gene expression misregulation inany type of NER deficient cells found in Xeroderma Pigmentosum patients.