Histone Mutants Separate R Loop Formation from Genome Instability Induction

R loops have positive physiological roles, but they can also be deleterious by causing genome instability, and the mechanisms for this are unknown. Here we identified yeast histone H3 and H4 mutations that facilitate R loops but do not cause instability. R loops containing single-stranded DNA (ssDNA...

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Published in:	Molecular cell Vol. 66; no. 5; pp. 597 - 609.e5
Main Authors:	García-Pichardo, Desiré, Cañas, Juan C., García-Rubio, María L., Gómez-González, Belén, Rondón, Ana G., Aguilera, Andrés
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-06-2017
Subjects:	chromatin Chromatin - chemistry Chromatin - genetics Chromatin - metabolism Chromatin Assembly and Disassembly chromatin compaction chromosome fragility DNA Damage DNA Helicases - genetics DNA Helicases - metabolism DNA, Fungal - chemistry DNA, Fungal - genetics DNA, Fungal - metabolism genome instability Genome, Fungal Genomic Instability H3 serine-10 phosphorylation Histones - chemistry Histones - genetics Histones - metabolism histones H3 and H4 Nuclear Proteins - genetics Nuclear Proteins - metabolism Nucleic Acid Conformation Phosphorylation Point Mutation Protein Conformation Protein Processing, Post-Translational R loops RNA Helicases - genetics RNA Helicases - metabolism RNA, Fungal - chemistry RNA, Fungal - genetics RNA, Fungal - metabolism RNA-DNA hybrids Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - metabolism Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Structure-Activity Relationship R loops genome instability histones H3 and H4 RNA-DNA hybrids H3 serine-10 phosphorylation chromosome fragility chromatin chromatin compaction
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Summary:	R loops have positive physiological roles, but they can also be deleterious by causing genome instability, and the mechanisms for this are unknown. Here we identified yeast histone H3 and H4 mutations that facilitate R loops but do not cause instability. R loops containing single-stranded DNA (ssDNA), versus RNA-DNA hybrids alone, were demonstrated using ssDNA-specific human AID and bisulfite. Notably, they are similar size regardless of whether or not they induce genome instability. Contrary to mutants causing R loop-mediated instability, these histone mutants do not accumulate H3 serine-10 phosphate (H3S10-P). We propose a two-step mechanism in which, first, an altered chromatin facilitates R loops, and second, chromatin is modified, including H3S10-P, as a requisite for compromising genome integrity. Consistently, these histone mutations suppress the high H3S10 phosphorylation and genomic instability of hpr1 and sen1 mutants. Therefore, contrary to what was previously believed, R loops do not cause genome instability by themselves. [Display omitted] •Histones represent a first barrier to R loop formation•R loops per se do not cause genetic instability•H3 serine-10 phosphorylation is required for R loop-mediated genetic instability•Histone mutants unable to phosphorylate H3S10 suppress hpr1 genome instability R loops can cause genome instability. However, García-Pichardo et al. identify histone H3/H4 mutants that demonstrate that R loops alone are not enough. Instead, further chromatin modifications, including H3 serine-10 phosphorylation, are necessary. They conclude that once R loops form, an additional chromatin modification step is required for genome instability.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-2765 1097-4164
DOI:	10.1016/j.molcel.2017.05.014