p53 restoration suppresses retrotransposon-driven chromosomal instability through nonlinear let-7 feedback and stochastic burst control

Long-read sequencing has revealed that concurrent LINE-1 (L1) retrotransposition events on non-homologous chromosomes frequently generate reciprocal chromosomal translocations early in tumorigenesis, establishing retrotransposons as active drivers of structural genome evolution (1). Endogenous mechanisms that constrain L1-mediated chromosomal instability remain incompletely defined. p53 transcriptionally induces tristetraprolin (TTP/ZFP36) and let-7 microRNAs, both directly and indirectly via repression of the MYC-LIN28 oncogenic axis (2). Mature let-7 suppresses human L1 retrotransposition by binding L1 mRNA and impairing ORF2p translation (3). Here we integrate these findings into a nonlinear dynamical systems model linking p53 activation, MYC-LIN28-let-7 feedback, and L1 RNA kinetics. Deterministic analysis uncovers bistability, with a sharp p53 activation threshold separating genome-unstable (high L1) and genome-stable (low L1) attractor states. Stochastic simulations reproduce the punctuated, clustered insertion patterns observed in tumors. Modest p53 restoration disproportionately collapses burst frequency, reducing cumulative structural rearrangement burden--including reciprocal translocations--by >70% under moderate assumptions. These results reposition p53 restoration as a threshold-dependent, retrotransposon-restrictive strategy to limit early genomic diversification and clonal evolution in cancer, with implications for pharmacologic reactivation therapies.