PARP1 ADP-ribosylates lysine residues of the core histone tails

Messner, Simon; Altmeyer, Matthias; Zhao, Hongtao; Pozivil, Andrea; Roschitzki, Bernd; Gehrig, Peter; Rutishauser, Dorothea; Huang, Danzhi; Caflisch, Amedeo; Hottiger, Michael O.

doi:10.1093/nar/gkq463

Cited by 235 publications

(213 citation statements)

References 48 publications

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“…generate long branched chains of poly(ADP-ribose) (PAR) 6 , covalently attached to lysines on PARP1 itself 7 as well as chromatin-components such as histones [8][9][10] .…”

mentioning

confidence: 99%

The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks

Ali¹,

Timinszky²,

Arribas-Bosacoma³

et al. 2012

Nat Struct Mol Biol

220

196

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Poly(ADP-ribose) polymerase I (PARP1) is a primary DNA damage sensor whose (ADP-ribose) polymerase activity is acutely regulated by interaction with DNA breaks. Upon activation at sites of DNA damage, PARP1 modifies itself and other proteins by covalent addition of long branched polymers of ADP-ribose, which in turn recruit downstream DNA repair and chromatin remodelling factors. PARP1 recognizes DNA damage through its N-terminal DNA-binding domain (DBD), which consists of a tandem repeat of an unusual zinc-finger (ZnF) domain. We have now determined the crystal structure of the human PARP1-DBD bound to a DNA break. Along with functional analysis of PARP1 recruitment to sites of DNA damage in vivo, the structure reveals a dimeric assembly whereby ZnF1 and ZnF2 domains from separate PARP1 molecules form a strand-break recognition module that helps activate PARP1 by facilitating its dimerization and consequent trans-automodification.Short-patch repair of DNA single-strand breaks is initiated by poly(ADP-ribose) polymerase-1 (PARP1) -a multi-domain enzyme activated by binding of its N-terminal DNA-binding domain (DBD) to DNA breaks [1][2][3][4][5] . Activated PARP1 utilises NAD + to Correspondence to: Andreas G. Ladurner; Laurence H. Pearl; Antony W. Oliver. AUTHOR CONTRIBUTIONS A.A.E.A. purified the protein, crystallized the complex and collected the X-ray diffraction data; G.T. designed and constructed the PARP1-EGFP constructs and performed the laser DNA damage experiments; M.K. performed the FRAP experiments; P.O.H. engineered the knockdown PARP1 cell line and the wild-type imaging reporter constructs, and performed the in vitro complementation assays; M.H. and R.A.-B. engineered and purified mutant PARP1 constructs; A.G.L. designed the study and analysed the data; L.H.P designed the study, analysed the data and wrote the paper; A.W.O. made the baculovirus constructs, designed the purification protocol, and solved and refined the crystal structure. All authors discussed the results and commented on the manuscript. We have now determined the crystal structure of the DNA-binding domain of PARP1 (PARP1-DBD) encompassing the first two zinc-finger (ZnF) domains, bound to a DNA break. In contrast with structural analysis of the separated domains 22 , we show that DNA binding by both zinc-finger domains is essential to damage recruitment in vivo, and that ZnF1 and ZnF2 domains from separate PARP1 molecules act as a functional unit to generate a dimeric binding module that specifically recognizes the single-strand / double-strand transition at a recessed DNA break. Mutational analysis in vitro and in cells demonstrates the functional requirement for zinc-finger dimerisation and reveals a mechanism for bringing two PARP1 molecules into close proximity at a DNA break as a prerequisite for transmodification. RESULTS Structure of the PARP1-DBD -DNA ComplexAn N-terminal segment of human PARP1 (residues 5-202) was expressed in insect cells and purified by column chromatography. Screening with a range of DNA molecules...

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“…generate long branched chains of poly(ADP-ribose) (PAR) 6 , covalently attached to lysines on PARP1 itself 7 as well as chromatin-components such as histones [8][9][10] .…”

mentioning

confidence: 99%

The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks

Ali¹,

Timinszky²,

Arribas-Bosacoma³

et al. 2012

Nat Struct Mol Biol

220

196

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“…The ADP ribosylation is read by zinc finger domains or macrodomains, which regulate the chromatin structure and transcription accordingly. Furthermore, the histone ADP ribosylation can be considered an additional component of the histone code (292)(293)(294).…”

Section: Figmentioning

confidence: 99%

The Genomes of Three Uneven Siblings: Footprints of the Lifestyles of Three Trichoderma Species

Schmoll

Dattenböck

Carreras-Villaseñor

et al. 2016

Microbiol Mol Biol Rev

163

195

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SUMMARYThe genusTrichodermacontains fungi with high relevance for humans, with applications in enzyme production for plant cell wall degradation and use in biocontrol. Here, we provide a broad, comprehensive overview of the genomic content of these species for “hot topic” research aspects, including CAZymes, transport, transcription factors, and development, along with a detailed analysis and annotation of less-studied topics, such as signal transduction, genome integrity, chromatin, photobiology, or lipid, sulfur, and nitrogen metabolism inT. reesei,T. atroviride, andT. virens, and we open up new perspectives to those topics discussed previously. In total, we covered more than 2,000 of the predicted 9,000 to 11,000 genes of eachTrichodermaspecies discussed, which is >20% of the respective gene content. Additionally, we considered available transcriptome data for the annotated genes. Highlights of our analyses include overall carbohydrate cleavage preferences due to the different genomic contents and regulation of the respective genes. We found light regulation of many sulfur metabolic genes. Additionally, a new Golgi 1,2-mannosidase likely involved inN-linked glycosylation was detected, as were indications for the ability ofTrichodermaspp. to generate hybrid galactose-containingN-linked glycans. The genomic inventory of effector proteins revealed numerous compounds unique toTrichoderma, and these warrant further investigation. We found interesting expansions in theTrichodermagenus in several signaling pathways, such as G-protein-coupled receptors, RAS GTPases, and casein kinases. A particularly interesting feature absolutely unique toT. atrovirideis the duplication of the alternative sulfur amino acid synthesis pathway.

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“…Poly-ADP ribosylation of histones occurs at all histone proteins as well (Quenet et al, 2009;Messner et al, 2010), and is catalyzed by Poly (ADP-ribose) polymerases such as PARP1 and PARP2, with NAD + acting as a substrate. Likewise, poly-ADP ribosylation is reversed by poly (ADPribose)glycohydrolase (Quenet et al, 2009).…”

Section: Other Histone Modifications: Ubiquitination and Poly-adp Ribmentioning

confidence: 99%

Epigenetic Treatments for Cognitive Impairments

Day

Sweatt

2011

Neuropsychopharmacol

109

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Epigenetic mechanisms integrate signals from diverse intracellular transduction cascades and in turn regulate genetic readout. Accumulating evidence has revealed that these mechanisms are critical components of ongoing physiology and function in the adult nervous system, and are essential for many cognitive processes, including learning and memory. Moreover, a number of psychiatric disorders and syndromes that involve cognitive impairments are associated with altered epigenetic function. In this review, we will examine how epigenetic mechanisms contribute to cognition, consider how changes in these mechanisms may lead to cognitive impairments in a range of disorders and discuss the potential utility of therapeutic treatments that target epigenetic machinery. Finally, we will comment on a number of caveats associated with interpreting epigenetic changes and using epigenetic treatments, and suggest future directions for research in this area that will expand our understanding of the epigenetic changes underlying cognitive disorders.

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PARP1 ADP-ribosylates lysine residues of the core histone tails

Cited by 235 publications

References 48 publications

The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks

The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks

The Genomes of Three Uneven Siblings: Footprints of the Lifestyles of Three Trichoderma Species

Epigenetic Treatments for Cognitive Impairments

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