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Post-transcriptional polyadenylation site cleavage maintains 3'-end processing upon DNA damage

ABSTRACT: The recognition of polyadenylation signals (PAS) in eukaryotic pre-mRNAs is usually coupled to transcription termination, occurring while pre-mRNA is chromatin-bound. However, for some pre-mRNAs, this 3'-end processing occurs post-transcriptionally, i.e. through a co-transcriptional cleavage (CoTC) event downstream of the PAS, leading to chromatin release and subsequent PAS cleavage in the nucleoplasm. While DNA-damaging agents trigger shutdown of co-transcriptional chromatin-associated 3ʹ-end processing, specific compensatory mechanisms exist to ensure efficient 3'-end processing for certain pre-mRNAs, 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-transcriptionally following a co-transcriptional cleavage event. Cells with an engineered deletion of the p53 CoTC site exhibit impaired p53 3'-end processing, decreased mRNA and protein levels of p53 and its transcriptional target p21, and altered cell cycle progression upon UV-induced DNA damage. Using a transcriptome-wide analysis of PAS cleavage, we identify additional pre-mRNAs whose PAS cleavage is maintained in response to UV irradiation and occurring post-transcriptionally. These findings indicate that CoTC-type cleavage of pre-mRNAs, followed by PAS cleavage in the nucleoplasm, allows specific certain pre-mRNAs to escape 3'-end processing inhibition in response to UV-induced DNA damage.

SUBMITTER: Dr. Rym Sfaxi

PROVIDER: S-SCDT-10_15252-EMBJ_2022112358 | biostudies-other |

REPOSITORIES: biostudies-other

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Post-transcriptional polyadenylation site cleavage maintains 3'-end processing upon DNA damage.

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