Title | Long non-coding RNA generated from CDKN1A gene by alternative polyadenylation regulates p21 expression during DNA damage response. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Murphy MR, Ramadei A, Doymaz A, Varriano S, Natelson DM, Yu A, Aktas S, Mazzeo M, Mazzeo M, Zakusilo G, Kleiman FE |
Journal | Nucleic Acids Res |
Volume | 51 |
Issue | 21 |
Pagination | 11911-11926 |
Date Published | 2023 Nov 27 |
ISSN | 1362-4962 |
Keywords | Cell Cycle, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, Humans, Polyadenylation, Protein Isoforms, RNA, Long Noncoding, Tumor Suppressor Protein p53 |
Abstract | Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DDR-activated APA event occurs in the first intron of CDKN1A, inducing an alternate last exon-containing lncRNA. We named this lncRNA SPUD (Selective Polyadenylation Upon DNA Damage). SPUD localizes to polysomes in the cytoplasm and is detectable as multiple isoforms in available high-throughput studies. SPUD has low abundance compared to the CDKN1A full-length isoform under non-stress conditions, and SPUD is induced in cancer and normal cells under a variety of DNA damaging conditions in part through p53. The RNA binding protein HuR binds to and promotes the stability of SPUD precursor RNA. SPUD induction increases p21 protein, but not mRNA levels, affecting p21 functions in cell-cycle, CDK2 expression and cell growth. Like CDKN1A full-length isoform, SPUD can bind two competitive p21 translational regulators, the inhibitor calreticulin and the activator CUGBP1; SPUD alters their association with CDKN1A full-length in a DDR-dependent manner, promoting CDKN1A translation. Together, these results show a new regulatory mechanism by which a lncRNA controls p21 expression post-transcriptionally, highlighting lncRNA relevance in DDR progression and cell-cycle. |
DOI | 10.1093/nar/gkad899 |
Alternate Journal | Nucleic Acids Res |
PubMed ID | 37870464 |
PubMed Central ID | PMC10681730 |
Grant List | U54 CA221704 / CA / NCI NIH HHS / United States R21 CA204610-01 / CA / NCI NIH HHS / United States / NH / NIH HHS / United States |
Submitted by bel2021 on February 16, 2024 - 10:41am