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High-LET radiation elicits qualitatively distinct biological responses at low versus high doses ( From DNA Damage to Stable Phenotype: The Role of the DDRcGASSTING Axis A critical question is how a transient physical insult (irradiation) induces stable, heritable changes in the cellular operating system. We propose that complex, clustered DNA double-strand breaks (DSBs) generated by high-LET heavy ions are the initiating trigger ( Beyond Epigenetic and Transcriptional Reprogramming: Genomic Scars as a Foundation for Phenotypic Stability Beyond epigenetic and transcriptional reprogramming, a fundamental mechanism driving the observed stable phenotypes may reside in the permanent genomic alterations elicited by high-LET radiation

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