Nucleotide Excision Repair controls RNA polymerase II levels.

MUÑOZ, JUAN C.; BECKERMAN, INÉS; CHOUDHARY, RAMVEER; BOUVIER, LEÓN ALBERTO; FOIANI, MARCO; MUÑOZ, MANUEL J.

Ottawa

Simposio; 13th International Conference on Environmental Mutagens (ICEM), 53rd Annual Meeting of the Environmental Mutagenesis and Genomics Society (EMGS); 2022

Environmental Mutagenesis and Genomics Society (EMGS)

RPB1, the major and catalytic subunit of human RNA Polymerase II (RNAPII), is specifically degraded by the ubiquitin-proteasome system upon UV-induced DNA damage. Current RNAPII degradation models exclusively rely on in cis degradation, where a stalled RNAPII functions as a lesion recognition factor that is later degraded in 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 through XPE and XPC and shares with TC-NER the core NER factors involved in the actual repair. Here we show that in a second phase after UV irradiation, and when TC-NER is no longer active, RNAPII degradation is prevented in cells lacking XPE and XPC and, therefore, triggered in trans by GG-NER. Accordingly with an in trans mechanism, UV-induced RNAPII degradation is not restricted to phosphorylated or chromatin bound RNAPII molecules. Finally, and further strengthening the role of NER in the control of RNAPII levels, incomplete lesion repair due to absence of any core NER factor induce an enhancement in RNAPII degradation, demonstrating that the signaling for RNAPII degradation is started by lesion recognition, either by TC- or GG-NER, and ends after the repair process is complete. These findings provide a rationale for gene expression misregulation in any type of NER deficient cells found in Xeroderma Pigmentosum patients.