MYST opportunities for growth control: yeast genes illuminate human cancer gene functions

Lafon, Anne; Chang, Christie S.; Scott, Erin M.; Jacobson, Sandra J.; Pillus, Lorraine

doi:10.1038/sj.onc.1210606

Cited by 63 publications

(53 citation statements)

References 119 publications

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“…As previously reported, deletion of GAS1 did not alter levels of H3K9Ac, H3K14Ac at 30° ( Koch and Pillus 2009), which are targets of both Gcn5 and Sas3 (reviewed in Lafon et al 2007). At 37°, a condition under which deletion of SAS3 suppresses gas1 temperature sensitivity, neither the gas1 strain nor gas1 sas3 had altered global levels of H3K9Ac, H3K14Ac ( Figure S2).…”

Section: Resultssupporting

confidence: 55%

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Unexpected Function of the Glucanosyltransferase Gas1 in the DNA Damage Response Linked to Histone H3 Acetyltransferases in Saccharomyces cerevisiae

Eustice

Pillus

2014

Genetics

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Chromatin organization and structure are crucial for transcriptional regulation, DNA replication, and damage repair. Although initially characterized in remodeling cell wall glucans, the b-1,3-glucanosyltransferase Gas1 was recently discovered to regulate transcriptional silencing in a manner separable from its activity at the cell wall. However, the function of Gas1 in modulating chromatin remains largely unexplored. Our genetic characterization revealed that GAS1 had critical interactions with genes encoding the histone H3 lysine acetyltransferases Gcn5 and Sas3. Specifically, whereas the gas1 gcn5 double mutant was synthetically lethal, deletion of both GAS1 and SAS3 restored silencing in Saccharomyces cerevisiae. The loss of GAS1 also led to broad DNA damage sensitivity with reduced Rad53 phosphorylation and defective cell cycle checkpoint activation following exposure to select genotoxins. Deletion of SAS3 in the gas1 background restored both Rad53 phosphorylation and checkpoint activation following exposure to genotoxins that trigger the DNA replication checkpoint. Our analysis thus uncovers previously unsuspected functions for both Gas1 and Sas3 in DNA damage response and cell cycle regulation.

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Section: Resultssupporting

confidence: 55%

“…Gcn5 and Sas3 share nucleosomal H3 targets (reviewed in Lafon et al 2007) and deletion of both GCN5 and SAS3 is synthetically lethal (Howe et al 2001). Further, both Gcn5 and Sas3 are recruited to similar genomic regions (Rosaleny et al 2007).…”

mentioning

confidence: 99%

Unexpected Function of the Glucanosyltransferase Gas1 in the DNA Damage Response Linked to Histone H3 Acetyltransferases in Saccharomyces cerevisiae

Eustice

Pillus

2014

Genetics

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“…It is now known that MYST proteins have important roles in various biological processes (Ceol and Horvitz, 2004;Kusch et al, 2004;Dou et al, 2005;Smith et al, 2005;Mendjan et al, 2006;Sykes et al, 2006;Tang et al, 2006). These enzymes have been the subjects of several excellent reviews Squatrito et al, 2006;Avvakumov and Coˆte´, 2007;Lafon et al, 2007;Rea et al, 2007;Thomas and Voss, 2007). MOZ and MORF are quite different from other members of this family (Figure 1), so we devote the following sections to this pair of HATs.…”

Section: Identification Of Moz Morf and Other Mystic Hatsmentioning

confidence: 99%

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

2007

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Genes of the human monocytic leukemia zinc-finger protein MOZ (HUGO symbol, MYST3) and its paralog MORF (MYST4) are rearranged in chromosome translocations associated with acute myeloid leukemia and/or benign uterine leiomyomata. Both proteins have intrinsic histone acetyltransferase activity and are components of quartet complexes with noncatalytic subunits containing the bromodomain, plant homeodomain-linked (PHD) finger and proline-tryptophan-tryptophan-proline (PWWP)-containing domain, three types of structural modules characteristic of chromatin regulators. Although leukemia-derived fusion proteins such as MOZ-TIF2 promote self-renewal of leukemic stem cells, recent studies indicate that murine MOZ and MORF are important for proper development of hematopoietic and neurogenic progenitors, respectively, thereby highlighting the importance of epigenetic integrity in safeguarding stem cell identity.

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“…GAS1 also exhibited a growth defect with deletion of EAF1 or a conditional allele of ESA1 (15), which both encode subunits of the nucleosomal acetylation of H4 (NuA4) complex (reviewed in ref. 16) that functions in silencing at the telomeres and rDNA (17). The basis for these interactions has not been pursued, but they suggest that GAS1 and ORC2, ESA1, and EAF1 may contribute to parallel processes that are critical for cellular function and viability.…”

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confidence: 99%

The glucanosyltransferase Gas1 functions in transcriptional silencing

Koch

Pillus

2009

Proc. Natl. Acad. Sci. U.S.A.

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Transcriptional silencing is a crucial process that is mediated through chromatin structure. The histone deacetylase Sir2 silences genomic regions that include telomeres, ribosomal DNA (rDNA) and the cryptic mating-type loci. Here, we report an unsuspected role for the enzyme Gas1 in locus-specific transcriptional silencing. GAS1 encodes a ␤-1,3-glucanosyltransferase previously characterized for its role in cell wall biogenesis. In gas1 mutants, telomeric silencing is defective and rDNA silencing is enhanced. We show that the catalytic activity of Gas1 is required for normal silencing, and that Gas1's role in silencing is distinct from its role in cell wall biogenesis. Established hallmarks of silent chromatin, such as Sir2 and Sir3 binding, H4K16 deacetylation, and H3K56 deacetylation, appear unaffected in gas1 mutants. Thus, another event required for telomeric silencing must be influenced by GAS1. Because the catalytic activity of Gas1 is required for telomeric silencing, Gas1 localizes to the nuclear periphery, and Gas1 and Sir2 physically interact, we propose a model in which carbohydrate modification of chromatin components provides a new regulatory element that may be critical for chromatin function but which is virtually unexplored in the current landscape of chromatin analysis.acetylation ͉ beta-glucan ͉ chromatin ͉ S. cerevisiae ͉ telomeres T he formation of silent chromatin leads to the transcriptional repression of regions of the genome. In the yeast Saccharomyces cerevisiae, these regions include the telomeres, ribosomal DNA (rDNA), and the cryptic mating-type loci (the HM loci, HML, and HMR), all of which require the silent information regulator 2 protein (Sir2), an NAD ϩ -dependent protein deacetylase (reviewed in ref. 1). Sir2 is the founding member of the conserved sirtuin deacetylase family (2), with Sir2 directing its activity toward lysine 16 of histone H4 (H4K16) to promote silent chromatin formation (reviewed in ref.3). There is also evidence that deacetylation of lysine 56 of histone H3 (H3K56) by Sir2 (4), or the sirtuins Hst3 and Hst4 (5), enables silencing at the telomeres and HM loci. Sir2 functions in the SIR complex with Sir3 and Sir4 to silence at telomeres, and also at the HM loci, where an additional protein, Sir1, also participates (1). However, within the rDNA, the Sir2 containing RENT complex acts independently of the other Sir proteins (1). Distinctions among the 3 silenced regions led to the hypothesis that different mechanisms of silent chromatin formation and regulation exist for each region.The basic model for silent chromatin formation at telomeres and HM loci involves recruitment of the SIR complex by DNA binding proteins, followed by Sir2-mediated histone deacetylation and additional SIR complex spreading. Hypoacetylation of histones enables silent chromatin spreading in the absence of Sir2 deacetylase activity, but is not sufficient for full silencing (6). Instead, deacetylase activity must be targeted to the silenced loci through Sir3 or some other means (7). Although...

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MYST opportunities for growth control: yeast genes illuminate human cancer gene functions

Cited by 63 publications

References 119 publications

Unexpected Function of the Glucanosyltransferase Gas1 in the DNA Damage Response Linked to Histone H3 Acetyltransferases in Saccharomyces cerevisiae

Unexpected Function of the Glucanosyltransferase Gas1 in the DNA Damage Response Linked to Histone H3 Acetyltransferases in Saccharomyces cerevisiae

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

The glucanosyltransferase Gas1 functions in transcriptional silencing

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