Epigenetic regulation of genome integrity by a prion-based mechanism

Abstract

ABSTRACTEpigenetic mechanisms mediate diverse gene expression programs in growth and development. Yet whether any can permanently alter the genome is unknown. Here we report a protein-based epigenetic element, a prion, formed by the conserved DNA helicase Mph1/FANCM. [MPH1+] provides resistance to DNA damage, a gain-of-function trait that requires helicase activity and interactions with other DNA repair proteins. Strikingly, the intrinsically disordered regions of Mph1 and human FANCM that are required for prion phenotypes do not resemble known prions. [MPH1+] reduces mitotic mutation rates, but promotes meiotic crossovers, driving phenotypic diversification in wild outcrosses. Remarkably, [MPH1+] is induced by stresses in which the prion is beneficial. Thus, [MPH1+] fuels a quasi-Lamarckian form of inheritance that promotes survival of the current generation and diversification of the next.