Histone H2B Deacetylation at Lysine 11 Is Required for Yeast Apoptosis Induced by Phosphorylation of H2B at Serine 10

Laboratory of Chromatin Biology, The Rockefeller University, Box 78, New York, New York 10021, USA.
Molecular Cell (Impact Factor: 14.02). 11/2006; 24(2):211-20. DOI: 10.1016/j.molcel.2006.09.008
Source: PubMed

ABSTRACT Chromatin alterations, induced by covalent histone modifications, mediate a wide range of DNA-templated processes, including apoptosis. Apoptotic chromatin condensation has been causally linked to the phosphorylation of histone H2B (serine 14 in human; serine 10 in yeast, H2BS10ph) in human and yeast cells. Here, we extend these studies by demonstrating a unidirectional, crosstalk pathway between H2BS10 phosphorylation and lysine 11 acetylation (H2BK11ac) in yeast. We demonstrate that the H2BK11 acetyl mark, which exists in growing yeast, is removed upon H(2)O(2) treatment but before H2BS10ph occurs, in a unidirectional fashion. H2B K11Q mutants are resistant to cell death elicited by H(2)O(2), while H2B K11R mutants that mimic deacetylation promote cell death. Our results suggest that Hos3 HDAC deacetylates H2BK11ac, which in turn mediates H2BS10ph by Ste20 kinase. Together, these studies underscore a concerted series of enzyme reactions governing histone modifications that promote a switch from cell proliferation to cell death.

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    • "Other than histone H2AX and H2B phosphorylation, little is known about other modifications to apoptotic chromatin, but histone deacetylation appears critical in at least some cases. Deacetylation of yeast histone H2B by the Hos3 HDAC (class II enzyme) is required for apoptosis [42], and apoptotic condensation in leukemia cells was linked with global histone deacetylation [43], but the deacetylases remain unknown. Given their involvement in heterochromatin formation at various genomic loci [6], sirtuins are reasonable candidates for apoptotic chromatin modifiers. "
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    ABSTRACT: The NAD(+)-dependent histone deacetylases, known as "sirtuins", participate in a variety of processes critical for single- and multi-cellular life. Recent studies have elucidated the importance of sirtuin activity in development, aging, and disease; yet, underlying mechanistic pathways are not well understood. Specific sirtuins influence chromatin structure and gene expression, but differences in their pathways as they relate to distinct chromatin functions are just beginning to emerge. To further define the range of global chromatin changes dependent on sirtuins, unique biological features of the ciliated protozoan Tetrahymena thermophila can be exploited. This system offers clear spatial and temporal separation of multiple whole genome restructuring events critical for the life cycle. Inhibition with nicotinamide revealed that sirtuin deacetylase activity in Tetrahymena cells promotes chromatin condensation during meiotic prophase, differentiation of heterochromatin from euchromatin during development, and chromatin condensation/degradation during programmed nuclear death. We identified a class I sirtuin, called Thd14, that resides in mitochondria and nucleoli during vegetative growth, and forms a large sub-nuclear aggregate in response to prolonged cell starvation that may be peripherally associated with nucleoli. During sexual conjugation and development Thd14 selectively concentrates in the parental nucleus prior to its apoptotic-like degradation. Sirtuin activity is important for several functionally distinct events requiring global chromatin condensation. Our findings suggest a novel role for sirtuins in promoting programmed pycnosis by acting on chromatin destined for degradation. The sirtuin Thd14, which displays physiological-dependent differential localization within the nucleus, is a candidate for a chromatin condensation enzyme that is coupled to nuclear degradation.
    BMC Cell Biology 09/2011; 12(1):40. DOI:10.1186/1471-2121-12-40 · 2.34 Impact Factor
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    • "Hos3 deacetylates histone H2B preferentially at position K11 as part of the apoptotic response to oxidative stress (Ahn et al., 2006). The enzyme displays site preferences toward acetylated lysines on each of the histone tails in vitro but no overt activity for H4K16 (Carmen et al., 1999). "
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    ABSTRACT: The yeast Sir2/3/4 complex forms a heterochromatin-like structure that represses transcription. The proteins nucleate at silencers and spread distally, utilizing the Sir2 NAD(+)-dependent histone deacetylase activity and the affinity of Sir3/4 for deacetylated histone tails. A by-product of the Sir2 reaction, O-acetyl-ADP-ribose (OAADPr), is thought to aid spreading by binding one of the Sir proteins. We developed a protein chimera approach to reexamine the contributions of Sir2. We show that a Sir3 chimera-bearing Hos3, an unrelated NAD(+)-independent histone deacetylase, substitutes for Sir2 in silencing. Sir3-Hos3 operates within the Sir pathway, spreading while deacetylating histones. Moreover, the chimera represses HM loci in strains lacking all five OAADPr-producing deacetylases, indicating that OAADPr is not necessary for silencing. Repression by a Hos3 hybrid bearing the targeting motifs of Sir2 shows that targeting doesn't require the Sir2 reaction. Together, these data demonstrate that protein deacetylation is the only essential function of Sir2 in creating silenced chromatin.
    Molecular cell 10/2008; 31(5):650-9. DOI:10.1016/j.molcel.2008.06.020 · 14.02 Impact Factor
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    • "Histone acetyltransferases and deacetylases X-J Yang and E Seto lysine 9 and serine 10 of histone H3, as well as for serine 10 and lysine 11 of histone H2B (Ahn et al., 2006; Li et al., 2006). Third, HATs and HDACs are physically linked to other catalytic activities. "
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    ABSTRACT: Acetylation of the epsilon-amino group of a lysine residue was first discovered with histones in 1968, but the responsible enzymes, histone acetyltransferases and deacetylases, were not identified until the mid-1990s. In the past decade, knowledge about this modification has exploded, with targets rapidly expanding from histones to transcription factors and other nuclear proteins, and then to cytoskeleton, metabolic enzymes, and signaling regulators in the cytoplasm. Thus, protein lysine acetylation has emerged as a major post-translational modification to rival phosphorylation. In this issue of Oncogene, 19 articles review various aspects of the enzymes governing lysine acetylation, especially about their intimate links to cancer. To introduce the articles, we highlight here four central themes: (i) multisubunit enzymatic complexes; (ii) non-histone substrates in diverse cellular processes; (iii) interplay of lysine acetylation with other regulatory mechanisms, such as noncoding RNA-mediated gene silencing and activation; and (iv) novel therapeutic strategies and preventive measures to combat cancer and other human diseases.
    Oncogene 09/2007; 26(37):5310-8. DOI:10.1038/sj.onc.1210599 · 8.46 Impact Factor
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