Gladyshev, EugeneKleckner, Nancy2017-12-062017Gladyshev, Eugene, and Nancy Kleckner. 2017. “DNA sequence homology induces cytosine-to-thymine mutation by a heterochromatin-related pathway in Neurospora.” Nature genetics 49 (6): 887-894. doi:10.1038/ng.3857. http://dx.doi.org/10.1038/ng.3857.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493386Eukaryotic genomes contain substantial amounts of repetitive DNA organized in the form of constitutive heterochromatin and associated with repressive epigenetic modifications, such as H3K9me3 and C5-cytosine methylation (5mC). In the fungus Neurospora crassa, H3K9me3 and 5mC are catalyzed, respectively, by a conserved SUV39 histone methyltransferase DIM-5 and a DNMT1-like cytosine methyltransferase DIM-2. Here we show that DIM-2 can also mediate Repeat-Induced Point mutation (RIP) of repetitive DNA in N. crassa. We further show that DIM-2-dependent RIP requires DIM-5, HP1, and other known heterochromatin factors, implying the role of a repeat-induced heterochromatin-related process. Our previous findings suggest that the mechanism of repeat recognition for RIP involves direct interactions between homologous double-stranded (ds) DNA segments. We thus now propose that, in somatic cells, homologous dsDNA/dsDNA interactions between a small number of repeat copies can nucleate a transient heterochromatic state, which, on longer repeat arrays, may lead to the formation of constitutive heterochromatin.en-USJournal Article2017-12-0610.1038/ng.3857