PARTICLE, a Triplex-Forming Long ncRNA, Regulates Locus-Specific Methylation in Response to Low-Dose Irradiation

• Expression of tumor suppressor MAT2A is regulated by PARTICLE via triplex formation
• PARTICLE interacts with silencing complexes G9a and PRC2
• PARTICLE and MAT2A are candidate biomarkers in patient plasma post-radiotherapy
• Inverse dose response of PARTICLE challenges the radiation linear non-threshold rule

SummaryExposure to low-dose irradiation causes transiently elevated expression of the long ncRNA PARTICLE (gene PARTICLE, promoter of MAT2A-antisense radiation-induced circulating lncRNA). PARTICLE affords both a cytosolic scaffold for the tumor suppressor methionine adenosyltransferase (MAT2A) and a nuclear genetic platform for transcriptional repression. In situ hybridization discloses that PARTICLE and MAT2A associate together following irradiation. Bromouridine tracing and presence in exosomes indicate intercellular transport, and this is supported by ex vivo data from radiotherapy-treated patients. Surface plasmon resonance indicates that PARTICLE forms a DNA-lncRNA triplex upstream of a MAT2A promoter CpG island. We show that PARTICLE represses MAT2A via methylation and demonstrate that the radiation-induced PARTICLE interacts with the transcription-repressive complex proteins G9a and SUZ12 (subunit of PRC2). The interplay of PARTICLE with MAT2A implicates this lncRNA in intercellular communication and as a recruitment platform for gene-silencing machineries through triplex formation in response to irradiation.

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