the others (reviewed by Kelley and Kuroda, 1995). This observation suggests that these gene products must interact Dosage compensation is a regulatory process that and form a complex. Preliminary direct evidence for such insures that males and females have equal amounts of an interaction is provided by the observation that MSL-1 X-chromosome gene products. In Drosophila, this is and MSL-2 can be co-precipitated with antisera against achieved by a 2-fold enhancement of X-linked gene either protein (Kelley et al., 1995). Binding of MLE and transcription in males, relative to females. The the MSL proteins to the X chromosome in males is enhancement of transcription is mediated by the correlated with the appearance of histone 4 acetylated at activity of a group of regulatory genes characterized Lys16 (H4Ac16) on the same chromosome (Turner et al., by the male-specific lethality of their loss-of-function 1992) and at the same sites (Bone et al., 1994). alleles. The products of these genes form a complexWe have used the phenotype of male-specific lethality that is preferentially associated with numerous sites on to screen the X chromosome of Drosophila melanogaster the X chromosome in somatic cells of males but not of for ethyl methane sulfonate (EMS)-induced mutations, females. Binding of the dosage compensation complex identifying additional genes that may be involved in the is correlated with a significant increase in the presence regulatory process of dosage compensation. We isolated of a specific histone isoform, histone 4 acetylated at one such mutation (mof) and observed that dying mutant Lys16, on this chromosome. Experimental results and males lack the X-associated isoform of H4Ac16. MOF sequence analysis suggest that an additional gene, exhibits the signature motif for the acetyl coenzyme males-absent on the first (mof), encodes a putative acetyl A binding site found in numerous and diverse acetyl transferase that plays a direct role in the specific histone transferases, and the mof mutation is a single amino acid acetylation associated with dosage compensation. The substitution in the most conserved residue of this motif. predicted amino acid sequence of MOF exhibits a This provides evidence that MOF is the histone acetyl significant level of similarity to several other proteins, transferase (HAT) responsible for the particular histone including the human HIV-1 Tat interactive protein acetylation involved in the male-specific hypertranscripTip60, the human monocytic leukemia zinc finger tion of X-linked genes. protein MOZ and the yeast silencing proteins SAS3 and SAS2.
Fragile X syndrome carriers have FMR1 alleles, called premutations, with an intermediate number of 5' untranslated CGG repeats between patients (>200 repeats) and normal individuals (<60 repeats). A novel neurodegenerative disease has recently been appreciated in some premutation carriers. As no neurodegeneration is seen in fragile X patients, who do not express FMR1, we hypothesize that lengthened rCGG repeats of the premutation transcript may lead to neurodegeneration. Here, using Drosophila melanogaster, we show that 90 rCGG repeats alone are sufficient to cause neurodegeneration. This phenotype is neuron specific and rCGG repeat dosage sensitive. Although devoid of mutant protein, this neurodegeneration exhibits neuronal inclusion bodies that are Hsp70 and ubiquitin positive. Overexpression of Hsp70 could suppress the neurodegeneration. These results demonstrate that neurodegenerative phenotype associated with fragile X premutation is indeed caused by the lengthened rCGG repeats and provide the first in vivo experimental demonstration of RNA-mediated neurodegeneration.
Posttranslational acetylation of core histone amino termini has long been associated with transcriptionally active chromatin. Recent reports have demonstrated histone acetyltransferase activity in a small group of conserved transcriptional regulators directly linked to gene activation. In addition, the presence of a putative acetyltransferase domain has been discovered in a group of proteins known as the MYST family (for its founding members MOZ, YBF2͞ SAS3, SAS2, and Tip60). Members of this family are implicated in acute myeloid leukemia (MOZ), transcriptional silencing in yeast (SAS2 and YBF2͞SAS3), HIV Tat interaction in humans (Tip60), and dosage compensation in Drosophila (MOF). In this report, we express a yeast ORF with homology to MYST family members and show it possesses histone acetyltransferase activity. Unlike the other MYST family members in Saccharomyces cerevisiae this gene is essential for growth.
We have determined that hMOF, the human ortholog of the Drosophila MOF gene (males absent on the first), encoding a protein with histone acetyltransferase activity, interacts with the ATM (ataxia-telangiectasiamutated) protein. Cellular exposure to ionizing radiation (IR) enhances hMOF-dependent acetylation of its target substrate, lysine 16 (K16) of histone H4 independently of ATM function. Blocking the IR-induced increase in acetylation of histone H4 at K16, either by the expression of a dominant negative mutant ⌬hMOF or by RNA interference-mediated hMOF knockdown, resulted in decreased ATM autophosphorylation, ATM kinase activity, and the phosphorylation of downstream effectors of ATM and DNA repair while increasing cell killing. In addition, decreased hMOF activity was associated with loss of the cell cycle checkpoint response to DNA double-strand breaks. The overexpression of wild-type hMOF yielded the opposite results, i.e., a modest increase in cell survival and enhanced DNA repair after IR exposure. These results suggest that hMOF influences the function of ATM.In eukaryotic cells, DNA damage activates signal transduction pathways that rapidly affect downstream processes such as gene transcription, cell cycle progression, and DNA replication (13,25). All of these processes involve alterations in chromatin structure. Posttranslational covalent modifications of histones have emerged as key regulatory events in DNA damage response. A widespread modification is acetylation catalyzed by histone acetyltransferases and reversed by deacetylases (3, 13, 50). Reversible acetylation of four lysines (K) at positions 5, 8, 12, and 16 in the amino-terminal tail of histone H4 occurs in vivo in all eukaryotes (3). The hyperacetylation of histone H4 could lead to the unfolding of the nucleosomal fiber (50), and the acetylation of histone H4 at K16 occurs on the hyperactive male X chromosome of Drosophila polytene chromosomes (51). Ikura et al. (19) noted that Tip60 (Tat-interacting protein), which acetylates histones H2A, H3, and H4, plays a role in DNA repair. More recently, Kusch et al. (28) demonstrated that the Drosophila Tip60 acetylates nucleosomal phosphoH2Av and exchanges it with an unmodified H2Av. Bird et al. (5) reported that the acetylation of histone H4 by Esa1 (essential SAS2-related acetyltransferase) is required for DNA repair in yeast and suggested that a similar modification may function in mammalian cells.ATM (ataxia-telangiectasia-mutated protein) is crucial for the initiation of signaling pathways in mammalian cells following exposure to ionizing radiation (IR) and other DNA-damaging agents (36, 46), and cells deficient in ATM function also have defective telomere chromatin (47). Bakkenist and Kastan (4) have suggested that chromatin structural perturbations induced by DNA double-strand breaks (DSBs) serve as a trigger for ATM activation. Recent studies indicate that the MRN (Mre11, Rad50, and Nbs1) complex as well as TRF2 either influences activation of ATM (9, 29, 52) or serves as a modulator/amp...
In many multicellular organisms, males have one X chromosome and females have two. Dosage compensation refers to a regulatory mechanism that insures the equalization of X-linked gene products in males and females. The mechanism has been studied at the molecular level in model organisms belonging to three distantly related taxa; in these organisms, equalization is achieved by shutting down one of the two X chromosomes in the somatic cells of females, by decreasing the level of transcription of the two doses of X-linked genes in females relative to males, or by increasing the level of transcription of the single dose of X-linked genes in males. The study of dosage compensation in these different forms has revealed the existence of an amazing number of interacting chromatin remodeling mechanisms that affect the function of entire chromosomes.
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