Chromatin immunoprecipitation with anti-acetyl histone H3 (K9 and K14) and anti-acetyl histone H4 (K5, K8, K12, and K16) antibodies shows that Lys-9 and͞or Lys-14 of histone H3, but not the relevant sites of histone H4 in nucleosomes at the repressed MFA2 promoter, are hyperacetylated after UV irradiation. This level of histone hyperacetylation diminishes gradually as repair proceeds. Accompanying this, chromatin in the promoter becomes more accessible to restriction enzymes after UV irradiation and returns to the pre-UV state gradually. UV-related histone hyperacetylation and chromatin remodeling in the MFA2 promoter depend on Gcn5p and partially on Swi2p, respectively. Deletion of GCN5, but not of SWI2, impairs repair of DNA damage in the MFA2 promoter. The post-UV histone modifications and chromatin remodeling at the repressed MFA2 promoter do not activate MFA2 transcriptionally, nor do they require damage recognition by Rad4p or Rad14p. Furthermore, we show that UV irradiation triggers genome-wide histone hyperacetylation at both histone H3 and H4. These experiments indicate that chromatin at a yeast repressed locus undergoes active change after UV radiation treatment and that failure to achieve histone H3 hyperacetylation impairs the repair of DNA damage.nucleotide ͉ excision repair ͉ Saccharomyces cerevisiae P ackaging DNA into chromatin constrains the genome into the cell nucleus and plays important roles in DNA metabolism. The dynamics of chromatin are finely regulated to control DNA function in response to various stimuli. During activation of gene expression the binding of transcriptional activators and coactivators to promoters results in perturbation of repressive chromatin in the promoter. These events facilitate access of subsequent incoming transcriptional factors to DNA. The changes in repressive chromatin often include chromatin remodeling by various complexes, e.g., SWI͞SNF, and acetylation of histones by histone acetyltransferases, e.g., Gcn5p (1, 2).The regulatory roles of histone acetylation and chromatin remodeling, although well documented, are largely confined to transcription initiation. Their roles in other events such as nucleotide excision repair (NER) that also operates on a chromatin template are only beginning to be explored. NER is a DNA repair pathway with Ͼ30 proteins involved in removing damage from naked DNA (3, 4). Studies have shown that the overall repair of DNA damage by NER is less efficient in reconstituted nucleosomes than in naked DNA (5-7), giving an indication that nucleosomes on damaged DNA inhibit efficient NER. In vivo, early studies with human cells showed that increasing the histone acetylation level overall in chromatin by inhibiting histone deacetylase activities enhances repair synthesis during NER (8-12). Chromatin rearrangement during repair synthesis in NER was also observed as newly repaired DNA in human fibroblasts is more sensitive to nuclease than bulk DNA in chromatin. The nascent repair patch lacks a canonical nucleosome DNase I footprinting, and thi...

High tumor burden is associated with increased levels of circulating inflammatory cytokines that influence the pathophysiology of the tumor and its environment. The cellular and molecular events mediating the organismal response to a growing tumor are poorly understood. Here, we report a bidirectional crosstalk between epithelial tumors and the fat body-a peripheral immune tissue-in Drosophila. Tumors trigger a systemic immune response through activation of Eiger/TNF signaling, which leads to Toll pathway upregulation in adipocytes. Reciprocally, Toll elicits a non-tissue-autonomous program in adipocytes, which drives tumor cell death. Hemocytes play a critical role in this system by producing the ligands Spätzle and Eiger, which are required for Toll activation in the fat body and tumor cell death. Altogether, our results provide a paradigm for a long-range tumor suppression function of adipocytes in Drosophila, which may represent an evolutionarily conserved mechanism in the organismal response to solid tumors.

SummaryThe control of systemic metabolic homeostasis involves complex inter-tissue programs that coordinate energy production, storage, and consumption, to maintain organismal fitness upon environmental challenges. The mechanisms driving such programs are largely unknown. Here, we show that enteroendocrine cells in the adult Drosophila intestine respond to nutrients by secreting the hormone Bursicon α, which signals via its neuronal receptor DLgr2. Bursicon α/DLgr2 regulate energy metabolism through a neuronal relay leading to the restriction of glucagon-like, adipokinetic hormone (AKH) production by the corpora cardiaca and subsequent modulation of AKH receptor signaling within the adipose tissue. Impaired Bursicon α/DLgr2 signaling leads to exacerbated glucose oxidation and depletion of energy stores with consequent reduced organismal resistance to nutrient restrictive conditions. Altogether, our work reveals an intestinal/neuronal/adipose tissue inter-organ communication network that is essential to restrict the use of energy and that may provide insights into the physiopathology of endocrine-regulated metabolic homeostasis.

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