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Genome-Wide Redistribution of H3k27me3 Is Linked to Genotoxic Stress and Defective Growth

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Genome-Wide Redistribution of H3k27me3 Is Linked to Genotoxic Stress and Defective Growth Genome-wide redistribution of H3K27me3 is linked to PNAS PLUS genotoxic stress and defective growth Evelina Y. Basenkoa,1, Takahiko Sasakia,1, Lexiang Jib, Cameron J. Prybola, Rachel M. Burckhardta, Robert J. Schmitzc, and Zachary A. Lewisa,2 aDepartment of Microbiology, University of Georgia, Athens, GA 30602; bInstitute of Bioinformatics, University of Georgia, Athens, GA 30602; and cDepartment of Genetics, University of Georgia, Athens, GA 30602 Edited by Jay C. Dunlap, Geisel School of Medicine at Dartmouth, Hanover, NH, and approved October 2, 2015 (received for review June 10, 2015) H3K9 methylation directs heterochromatin formation by recruiting silent chromatin. Pc-target domains are often referred to as fac- multiple heterochromatin protein 1 (HP1)-containing complexes ultative heterochromatin because these regions are condensed that deacetylate histones and methylate cytosine bases in DNA. and transcriptionally repressed in some but not all cell types In Neurospora crassa, a single H3K9 methyltransferase complex, (14). Polycomb repressive complex-2(PRC2)methylatesH3K27, called the DIM-5,-7,-9, CUL4, DDB1 Complex (DCDC), is required which in animals can be bound by PRC1 to promote mitotically for normal growth and development. DCDC-deficient mutants are heritable gene silencing (15, 16). However, the mechanisms that hypersensitive to the genotoxic agent methyl methanesulfonate control Pc complexes are not fully understood. In some situations, (MMS), but the molecular basis of genotoxic stress is unclear. We H3K27me3-independent recruitment of PRC1 can occur, leading found that both the MMS sensitivity and growth phenotypes of to subsequent PRC2 recruitment and deposition of H3K27me3 embryonic DCDC-deficient strains are suppressed by mutation of (17, 18). Pc components are absent from the model yeasts Sac- ectoderm development Su-(var)3-9; E(z); Trithorax (set)-7 or , charomyces cerevisiae and Schizosaccharyomyces pombe, whereas encoding components of the H3K27 methyltransferase Polycomb PRC1 appears to be absent from all fungi (19). PRC2 is present repressive complex-2 (PRC2). Trimethylated histone H3K27 (H3K27me3) in some fungi, however, and H3K27me3 directs transcriptional undergoes genome-wide redistribution to constitutive heterochro- repression of PRC2-target domains in Neurospora, Fusarium matin in DCDC- or HP1-deficient mutants, and introduction of an graminearum, Epichloë festucae, and Cryptococcus neoformans H3K27 missense mutation is sufficient to rescue phenotypes of (19–23). Thus, the application of microbial genetic approaches DCDC-deficient strains. Accumulation of H3K27me3 in heterochro- to study the Pc system in fungi can provide mechanistic insights matin does not compensate for silencing; rather, strains deficient for into this evolutionarily conserved chromatin regulatory system. both DCDC and PRC2 exhibit synthetic sensitivity to the topoisomer- Although the Pc system is best known for its ability to repress ase I inhibitor Camptothecin and accumulate γH2A at heterochro- matin. Together, these data suggest that PRC2 modulates the response developmentally regulated genes, recent studies in higher eukary- to genotoxic stress. otes link H3K27 methylation to DNA replication and repair. In human cancer cells, PRC2 associates more stably with chromatin Polycomb | heterochromatin | H3K9me3 | H3K27me3 | genotoxic stress following oxidative or UV-induced DNA damage, and levels of both PRC2 and H3K27me3 are increased at induced double-strand breaks(DSBs)(24–26). Moreover, knockdown of PRC2 increases ovalent modifications of histones and DNA partition ge- Cnomes into discrete functional domains. Heterochromatin refers to highly condensed parts of the genome that are tran- Significance scriptionally inert and rich in repeated DNA sequences (1). Failure to establish or maintain heterochromatin leads to cata- Regulators of chromatin structure play critical roles in DNA- strophic defects in chromosome segregation, DNA replication, based processes. Lysine (K) Methyltransferase 1 (KMT1) ho- and DNA repair, highlighting its functional importance (1–3). At mologs perform methylation of H3 lysine-9 and are best known the molecular level, heterochromatin domains are defined by for their essential role in heterochromatin formation and tran- hypoacetylated histones, histone H3K9 methylation (H3K9me), scriptional silencing. Heterochromatin formation is also important and DNA methylation (1). The fungus Neurospora crassa shares for maintenance of genome stability, although the mechanisms these features with higher eukaryotes and is an established model are not well understood. We report that altered activity of Poly- to study the control and function of heterochromatin (4). In comb repressive complex-2 (PRC2), a histone lysine-27 methyl- Neurospora, the H3K9 methyltransferase complex, named the transferase complex, is responsible for genotoxic stress, poor growth, and defective development in KMT1-deficient mutants of defective in methylation (DIM)-5,-7,-9, Cullin 4, DNA damage- Neurospora crassa binding protein 1 (DDB1) Complex (DCDC), initiates hetero- . Mammalian KMT1 and PRC2 are required for chromatin formation at degenerate DNA repeat sequences that development and are frequently mutated in cancer. This work are products of the genome defense system repeat-induced point provides information about the cellular consequences of KMT1 and PRC2 deficiency and provides insights into the regulatory and mutation (RIP) (5–7). DCDC trimethylates H3K9 to create binding functional relationships of these conserved enzymes. sites for multiple heterochromatin protein 1 (HP1)-containing complexes, which in turn direct methylation of cytosine bases in Author contributions: E.Y.B., T.S., R.J.S., and Z.A.L. designed research; E.Y.B., T.S., L.J., C.J.P., GENETICS DNA and deacetylation of histones (8–10). As in other eukary- and R.M.B. performed research; T.S. and C.J.P. contributed new reagents/analytic tools; E.Y.B., otes, heterochromatin formation is sufficient to silence transcription T.S., L.J., C.J.P., R.M.B., R.J.S., and Z.A.L. analyzed data; and Z.A.L. wrote the paper. in Neurospora. Reporter genes flanked by RIP’d DNA are not The authors declare no conflict of interest. expressed, and spreading of heterochromatin causes aberrant gene This article is a PNAS Direct Submission. silencing in strains that lack DNA methylation modulator-1 Data deposition: The sequence reported in this paper has been deposited in NCBI Short (DMM-1) (11, 12). Together, heterochromatin domains comprise Reads Archive (accession no. SRP058573). ∼20% of the Neurospora genome and include structurally im- 1E.Y.B. and T.S. contributed equally to this work. portant loci such as the centromeres (7, 13). 2To whom correspondence should be addressed. Email: [email protected]. In animals, plants, and some fungi, Polycomb (Pc) group pro- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. teins establish and maintain a second type of transcriptionally 1073/pnas.1511377112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1511377112 PNAS | Published online November 2, 2015 | E6339–E6348 Downloaded by guest on September 30, 2021 sensitivity to ionizing radiation (25). It is possible that Pc proteins strain. We identified a mutation in the gene encoding the PRC2 are recruited to silence transcription in the vicinity of a DNA lesion, component embryonic ectoderm development (EED) in mouse but the precise roles of PRC2 and H3K27me3 in the DNA damage (19, 47). H3K9me3-deficient mutants exhibit redistribution of response are unclear. H3K27me3, leading to induction of PRC2-target genes. We show Similarly, defects in constitutive heterochromatin formation that gain of H3K27me3 in constitutive heterochromatin domains are associated with genome instability. Replication fork stalling is not compensatory for gene silencing but rather leads to growth is observed in S. pombe heterochromatin domains (27), and defects and altered sensitivity to genotoxic agents. Our data Clr4KMT1-deficient mutants, which lack H3K9me2, exhibit ille- suggest that PRC2 modulates the response to genotoxic stress. gitimate mitotic recombination that is exacerbated by mutation of the replication fork protection complex (3, 28). In Drosophila, Results cytological studies revealed that H3K9me-deficient mutants ex- Δdim-5 mutants exhibit hypersensitivity to the DNA-damaging hibit spontaneous DSBs in heterochromatin, and it was proposed agent MMS, suggesting that the DIM-5KMT1 MTase is required for that this damage is due to defective DNA replication (2, 29, 30). normal DNA replication or repair (5). We examined growth of Mice lacking Lysine (K) Methyltransferase 1A (KMT1A) (SUV39H1) heterochromatin-defective mutants in the presence of additional and KMT1B (SUV39H2) exhibit genome instability and high DNA replication and repair inhibitors (Fig. 1A). As controls, rates of lymphoma development (31, 32), and both KMT1 en- we included mutagen-sensitive-9 (mus-9), lacking the Neurospora zymes and HP1 proteins have been implicated in DNA repair in ATM homolog required for the DNA damage response (48), and animals (33–42). These and other studies suggest that hetero- mei-3, lacking the Neurospora homolog of RAD51 required for chromatin components have important roles during both DNA homologous recombination (49). Elimination of DNA methylation replication and DNA repair, but the heterochromatin-dependent did not impact growth on any of the tested genotoxic agents. mechanisms
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