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However, for some pre\u2010mRNAs, this 3\u2032\u2010end processing occurs post\u2010transcriptionally, i.e., through a co\u2010transcriptional cleavage (CoTC) event downstream of the PAS, leading to chromatin release and subsequent PAS cleavage in the nucleoplasm. While DNA\u2010damaging agents trigger the shutdown of co\u2010transcriptional chromatin\u2010associated 3\u2032\u2010end processing, specific compensatory mechanisms exist to ensure efficient 3\u2032\u2010end processing for certain pre\u2010mRNAs, including those that encode proteins involved in the DNA damage response, such as the tumor suppressor p53. We show that cleavage at the p53 polyadenylation site occurs in part post\u2010transcriptionally following a co\u2010transcriptional cleavage event. Cells with an engineered deletion of the p53 CoTC site exhibit impaired p53 3\u2032\u2010end processing, decreased mRNA and protein levels of p53 and its transcriptional target p21, and altered cell cycle progression upon UV\u2010induced DNA damage. Using a transcriptome\u2010wide analysis of PAS cleavage, we identify additional pre\u2010mRNAs whose PAS cleavage is maintained in response to UV irradiation and occurring post\u2010transcriptionally. These findings indicate that CoTC\u2010type cleavage of pre\u2010mRNAs, followed by PAS cleavage in the nucleoplasm, allows certain pre\u2010mRNAs to escape 3\u2032\u2010end processing inhibition in response to UV\u2010induced DNA damage.<\/jats:p>","DOI":"10.15252\/embj.2022112358","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T03:32:14Z","timestamp":1675999934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Post\u2010transcriptional polyadenylation site cleavage maintains 3\u2032\u2010end processing upon DNA damage"],"prefix":"10.1038","volume":"42","author":[{"given":"Rym","family":"Sfaxi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-9854","authenticated-orcid":false,"given":"Biswendu","family":"Biswas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Boldina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Cadix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1678-7410","authenticated-orcid":false,"given":"Nicolas","family":"Servant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R","family":"Larson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0278-4120","authenticated-orcid":false,"given":"Martin","family":"Dutertre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Robert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1452-7164","authenticated-orcid":false,"given":"St\u00e9phan","family":"Vagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,10]]},"reference":[{"key":"BFEMBJ2022112358_CR1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S1097-2765(03)00492-1","volume":"13","author":"SH Ahn","year":"2004","unstructured":"Ahn SH, Kim M, Buratowski S (2004) Phosphorylation of serine 2 within the RNA polymerase II C\u2010terminal domain couples transcription and 3\u2032 end processing. 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