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Downregulation of TdT Expression through Splicing Modulation by Antisense Peptide Nucleic Acid (PNA)

Soheila Montazersaheb1,2,3, Masoumeh Kazemi1, Elahe Nabat1

  • 1Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Current Pharmaceutical Biotechnology
|February 8, 2019
PubMed
Abstract

Insights

Peptide nucleic acids (PNAs) effectively alter TdT pre-mRNA splicing, reducing TdT protein levels. This PNA-mediated approach induces apoptosis and decreases cell survival, offering a potential strategy for cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Oligonucleotide Chemistry

Background:

  • Antisense oligonucleotides modulate gene expression and splicing.
  • Terminal deoxynucleotidyl transferase (TdT) is a potential cancer therapeutic target.

Purpose of the Study:

  • Investigate TdT pre-mRNA splicing alteration in Molt-4 cells.
  • Utilize peptide nucleic acid (PNA) conjugates for TdT modulation.

Main Methods:

  • Examined 16-mer PNAs targeting intron 7 splice junctions.
  • Assessed splicing modulation via RT-PCR.
  • Analyzed TdT protein levels, apoptosis, and cell viability.

Main Results:

  • PNAs modulated TdT pre-mRNA splicing, producing longer mRNA variants.
  • Reduced TdT protein levels observed in PNA-treated Molt-4 cells.
  • PNA treatment increased apoptosis and decreased cell survival.

Conclusions:

  • PNA-mediated splicing modulation specifically downregulates TdT expression.
  • TdT downregulation induces apoptosis and reduces cell survival in Molt-4 cells.
  • PNA strategies show promise for TdT suppression in acute lymphoblastic leukemia.
Keywords:
AntisensePNA (peptide nucleic acid)TdTexon skippingintron retentionsplicing inhibition.

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