Modulation of PDCD1 exon 3 splicing.

Abstract:

:The PDCD1 gene encodes PD-1, an important immune checkpoint protein and key immunotherapy target to treat cancer. PDCD1 is alternatively spliced to generate an exon 3-skipped isoform PD-1Δ3 that has been suggested to play an antagonistic role to PD-1, but the mechanism underlying alternative splicing of PDCD1 has never been explored. Here using a minigene system, we analysed the splicing pattern of PDCD1 in multiple cell lines and confirmed exon 3 skipping as the main alternative splicing event. Using deletion analysis of exon 3, we mapped two splicing enhancers in the exon: ESE3a and ESE3b. Using mutagenesis, RNA-affinity chromatography, mass spectrometry as well as depletion and overexpression of MATR3, we defined MATR3 as a splicing activator during PDCD1 exon 3 splicing that operates through binding to ESE3b. MATR3's splicing-stimulatory activity is counteracted by an RNA secondary structure around ESE3b and an RNA helicase DDX5. Furthermore, we identified ASOs that efficiently promotes PDCD1 exon 3 skipping in both minigene and endogenous-gene contexts. Our data support further study of the ASOs as potential drug candidates to treat cancer.

journal_name

RNA Biol

journal_title

RNA biology

authors

Sun J,Bai J,Jiang T,Gao Y,Hua Y

doi

10.1080/15476286.2019.1659080

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

1794-1805

issue

12

eissn

1547-6286

issn

1555-8584

journal_volume

16

pub_type

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