Antisense Oligonucleotides Modulating Activation of a Nonsense-Mediated RNA Decay Switch Exon in the ATM Gene

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• ATM (ataxia-telangiectasia, mutated) is a crucial gene in DNA damage response and cancer susceptibility.
• ATM mutations cause ataxia-telangiectasia (A-T), a syndrome linked to DNA break hypersensitivity and lymphoid cancers.
• ATM expression is regulated by a nonsense-mediated RNA decay (NMD) switch exon (NSE) in intron 28.

Purpose of the Study:

• To identify antisense oligonucleotides (ASOs) capable of modulating NSE inclusion in ATM transcripts.
• To investigate the role of intronic elements, including transposons, in regulating NSE activity.
• To explore the potential of ASOs for sequence-specific cancer radiosensitization.

Main Methods:

• Systematic targeting of the 3.1-kb ATM intron 28 to identify splice-switching oligonucleotides.
• Segmental deletion analysis of intronic transposed elements to assess their effect on NSE.
• Delivery of optimized ASOs using chitosan-based nanoparticles to cells.

Main Results:

• Identification of ASOs that modulate NSE inclusion in ATM pre-mRNA.
• Demonstration that intronic elements, such as Alu and MER51A transposons, influence NSE regulation.
• Efficient NSE repression achieved via nanoparticle-mediated delivery of ASOs.

Conclusions:

• Intronic ASOs can effectively modify gene expression by targeting regulatory elements like NSE.
• Transposon activity plays a role in regulating NSEs, impacting ATM expression.
• These findings support the development of ASO-based strategies for cancer radiosensitization.