Long non-coding RNA generated from CDKN1A gene by alternative polyadenylation regulates p21 expression during DNA damage response

Author:

Murphy Michael R12,Ramadei Anthony12,Doymaz Ahmet1,Varriano Sophia12,Natelson Devorah M12,Yu Amy1,Aktas Sera1,Mazzeo Marie1,Mazzeo Michael1,Zakusilo George1,Kleiman Frida E12ORCID

Affiliation:

1. Chemistry Department, Hunter College, The City University of New York , New York , NY  10021 , USA

2. Biology Program, The Graduate Center, The City University of New York , New York , NY 10016 , USA

Abstract

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.

Funder

National Cancer Institute

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Genetics

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