<i>Drosophila</i>
            histone H2A variant (H2Av) controls poly(ADP-ribose) polymerase 1 (PARP1) activation in chromatin

Kotova, Elena; Lodhi, Niraj; Jarnik, Michael; Pinnola, Aaron D.; Ji, Yingbiao; Tulin, Adrian

doi:10.1073/pnas.1019644108

Cited by 71 publications

(93 citation statements)

References 44 publications

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“…Importantly, the S139 phosphorylation of H2AX in mammalian cells is not required for the dynamics of either H2AX or PARP-1 (9 and this study). Although this contradicts the results obtained from the study in a fly system, where the phosphorylation of the H2A variant (H2Av) controlled PARP-1 upon transcriptional activation, the discrepancy may be due to differences in the biological functions of the H2A variants in the different organisms (33).…”

Section: Discussioncontrasting

confidence: 74%

“…To facilitate the recruitment of transcription factors, the chromatin must be remodeled. Chromatin decondensation or histone exchange at transcription sites occurs in response to extracellular stress such as heat shock, and the activation of PARP-1 promotes this process (33,42,43). PARP-1 activation at transcription sites is likely to require nucleosomes, as they can accommodate PARP-1 (44).…”

Section: Discussionmentioning

confidence: 99%

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Coordinated Regulation of TIP60 and Poly(ADP-Ribose) Polymerase 1 in Damaged-Chromatin Dynamics

Ikura

Furuya

Fukuto

et al. 2016

Molecular and Cellular Biology

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fThe dynamic exchange of histones alleviates the nucleosome barrier and simultaneously facilitates various aspects of cellular DNA metabolism, such as DNA repair and transcription. In response to DNA damage, the acetylation of Lys5 in the histone variant H2AX, catalyzed by TIP60, plays a key role in promoting histone exchange; however, the detailed molecular mechanism still is unclear. Here, we show that the TIP60 complex includes poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 is required for the rapid exchange of H2AX on chromatin at DNA damage sites. It is known that PARP-1 binds dynamically to damaged chromatin and is crucial for the subsequent recruitment of other repair factors, and its auto-poly(ADP-ribosyl)ation is required for the dynamics. We also show that the acetylation of histone H2AX at Lys5 by TIP60, but not the phosphorylation of H2AX, is required for the ADP-ribosylation activity of PARP-1 and its dynamic binding to damaged chromatin. Our results indicate the reciprocal regulation of K5 acetylation of H2AX and PARP-1, which could modulate the chromatin structure to facilitate DNA metabolism at damage sites. This could explain the rather undefined roles of PARP-1 in various DNA damage responses. P osttranslational modifications of histones are a fundamental process for the chromatin remodeling machinery in DNA metabolism, including transcription, DNA replication, and DNA repair (1, 2). These histone modifications either serve as the binding interface for regulatory factors in chromatin reorganization or function as a platform in a signaling cascade, such as in the DNA damage checkpoint response (1, 3). In addition to histone modifications, the incorporation or eviction of histone variants regulates chromatin dynamics and could directly promote DNA metabolism in the context of chromatin (4-9). Thus, it is important to clarify how the histone variants' dynamics at DNA damage sites and their modifications are coordinated upon commitment to each type of DNA metabolism. Such clarification would promote a better understanding of the significance of histone variants, which potentially play active roles, rather than simply functioning as barriers, during DNA metabolism (10).Upon DNA damage, Ser139 (S139) of H2AX, a histone H2A variant, is phosphorylated at DNA damage sites, and the phosphorylated H2AX functions as an anchor to retain DNA damage response (DDR) factors on the DNA damage sites (11-14). We previously reported that the acetylation of H2AX at lysine 5 (K5Ac) is required to facilitate histone H2AX exchange at DNA damage sites and also is necessary for the efficient assembly of NBS1 at these sites by promoting its turnover rate (9, 15). K5 acetylation of H2AX is catalyzed by the histone acetyltransferase TIP60 complex, which coordinates the signaling and repair of DNA damage via chromatin reorganization (9, 16-18). Importantly, the phosphorylation of H2AX on S139 is not required to facilitate H2AX exchange or to promote NBS1 turnover at DNA damage sites (9, 15). These findings indicated the dist...

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Coordinated Regulation of TIP60 and Poly(ADP-Ribose) Polymerase 1 in Damaged-Chromatin Dynamics

Ikura

Furuya

Fukuto

et al. 2016

Molecular and Cellular Biology

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“…2C). His2Av 810 is a null allele that contains a 311 bp deletion that removes the region surrounding and including the second exon of the gene (van Daal and Elgin, 1992 (Kotova et al, 2011). In order to test whether the formation of the melanotic masses was due to the loss of H2AV, rather than some other unknown mutation in the genetic background of the homozygous animals, we crossed His2Av 810 /+ heterozygotes with flies heterozygous for Df(3R)BSC524, a large deletion mutant with molecularly defined endpoints in the same region of the genome (Cook et al, 2012).…”

Section: Loss Of H2av Causes Melanotic Masses In Drosophila Larvaementioning

confidence: 99%

The role of variant histone H2AV in Drosophila melanogaster larval hematopoiesis

2017

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Replication-independent histone variants can replace the canonical replication-dependent histones. Vertebrates have multiple H2A variant histones, including H2AZ and H2AX that are present in most eukaryotes. H2AZ regulates transcriptional activation as well as the maintenance of gene silencing, while H2AX is important in DNA damage repair. The fruit fly Drosophila melanogaster has only one histone H2A variant (H2AV), which is a chimera of H2AZ and H2AX. In this study we found that lack of H2AV led to the formation of black melanotic masses in Drosophila third instar larvae. The formation of these masses was found in conjunction with a loss of the majority of the primary lymph gland lobes. Interestingly, the cells of the posterior signaling center were preserved in these mutants. Reduction of H2AV levels by RNAi knockdown caused a milder phenotype that preserved the lymph gland structure but that included precocious differentiation of the prohemocytes located within the medullary zone and the secondary lobes of the lymph gland. Mutant rescue experiments suggest that the H2AZ-like rather than the H2AX-like function of H2AV is primarily required for normal hematopoiesis.

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“…Histone proteins are highly vulnerable to post-translational modification at specific amino acids. The covalent post-translational modifications include but are not limited to methylation (13), acetylation (14), phosphorylation (15), ubiquitination (16), sumoylation (17), biotinylation (18), and ADP-ribosylation (19). To date, only one study has recently demonstrated by mass screening histone S-palmitoylation; however, the identity of the acyltransferase that catalyzes this reaction was not investigated (20).…”

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confidence: 99%

Acyl-CoA:Lysophosphatidylcholine Acyltransferase I (Lpcat1) Catalyzes Histone Protein O-Palmitoylation to Regulate mRNA Synthesis

Zou¹,

Ellis²,

Smith³

et al. 2011

Journal of Biological Chemistry

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The enzyme acyl-CoA:lysophosphatidylcholine acyltransferase (Lpcat1) is a critical cytosolic enzyme needed for lung surfactant synthesis that catalyzes an acyltransferase reaction by adding a palmitate to the sn-2 position of lysophospholipids. Here we report that histone H4 protein is subject to palmitoylation catalyzed by Lpcat1 in a calcium-regulated manner. The enzyme acyl-CoA:lysophosphatidylcholine acyltransferase (Lpcat1) was recently cloned from lung epithelia and is indispensable for generation of pulmonary surfactant. Lpcat1 catalyzes an O-acyltransferase reaction by covalently adding saturated acyl-CoAs (palmitoyl groups, 16:0) to its acceptor lysophospholipids. Specifically, in the lung, it catalyzes an oxyester linkage between palmitate and lysophosphatidylcholine to generate dipalmitoylphosphatidylcholine, the major surface tension-lowering component of pulmonary surfactant in the remodeling pathway (1, 2). However, Lpcat1 appears to be somewhat promiscuous and acts on substrates that include lysophosphatidylcholine, lysoplasmanylcholine, and lysophosphatidylglycercol (1-3). Notably, in addition to lipid substrates, O-acyltransferases can also lipidate some protein substrates (4 -7). These enzymes share a highly conserved histidine residue within a catalytic core that is essential for their functionality.Protein palmitoylation, a prototypical form of lipidation, is an important post-translational modification that occurs ubiquitously in eukaryotes. Protein palmitoylation is generally categorized as S-palmitoylation, N-palmitoylation, and O-palmitoylation based on the chemical linkage between donor and acceptor substrates. Among these, S-palmitoylation is best characterized and involves generation of a reversible thioester bond between a cysteine residue and a palmitate group (8). As many as 250 proteins were found to be modified by S-palmitoylation in mammalian neurons, and these reactions are largely catalyzed by aspartate-histidine-histidine-cysteine (DHHC) palmitoyl acyltransferase family members (8, 9). The biochemistry of N-palmitoylation and O-palmitoylation, however, is less studied. One known substrate for N-palmitoylation is the Sonic Hedgehog protein because its NH 2 -terminal cysteine is palmitoylated via an amide linkage by Hedgehog acyltransferase (Hhat) (5). O-Palmitoylation is exemplified by Wnt/Wg proteins that harbor an oxyester linkage between monounsaturated palmitate and a serine residue. Another recently described O-palmitoylation target, the peptide hormone preghrelin, is modified by octanoylation at a serine residue. The enzymes that catalyze the oxyester linkages within Wnt/Wg proteins and preghrelin are porcupine (6) and ghrelin O-acyltransferase (7), respectively. The physiological consequences of palmitoylation are diverse; by increasing substrate hydrophobicity, these lipidation reactions appear to modulate interactions of substrates with other biomolecules, often affecting signal transduction, protein stability, intracellular trafficking, and localization (10 -12).Histo...

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Drosophila histone H2A variant (H2Av) controls poly(ADP-ribose) polymerase 1 (PARP1) activation in chromatin

Cited by 71 publications

References 44 publications

Coordinated Regulation of TIP60 and Poly(ADP-Ribose) Polymerase 1 in Damaged-Chromatin Dynamics

Coordinated Regulation of TIP60 and Poly(ADP-Ribose) Polymerase 1 in Damaged-Chromatin Dynamics

The role of variant histone H2AV in Drosophila melanogaster larval hematopoiesis

Acyl-CoA:Lysophosphatidylcholine Acyltransferase I (Lpcat1) Catalyzes Histone Protein O-Palmitoylation to Regulate mRNA Synthesis

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