Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil VSports app下载. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

Review
. 2010 Jul 9;39(1):8-24.
doi: 10.1016/j.molcel.2010.06.017.

"V体育官网" The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets

Raga Krishnakumar  1 , W Lee Kraus
Affiliations
Review

The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets

Raga Krishnakumar et al. Mol Cell. .

Abstract

The abundant nuclear enzyme PARP-1, a multifunctional regulator of chromatin structure, transcription, and genomic integrity, plays key roles in a wide variety of processes in the nucleus. Recent studies have begun to connect the molecular functions of PARP-1 to specific physiological and pathological outcomes, many of which can be altered by an expanding array of chemical inhibitors of PARP enzymatic activity. VSports手机版.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Structural and functional organization of PARP-1 and PARP-2
(A) Schematic representation of human PARP-1 and PARP-2 with the functional domains noted in the text. (B) Structures of the six structural and functional domains in human PARP-1. FI (PDB 2DMJ), FII (PDB 2CS2), FIII (PDB 2RIQ), BRCT (PDB 2COK), WGR (PDB: 2CR9), catalytic domain (PDB 1A26; NAD+ has been modeled in based on a structure of diptheria toxin, PDB 1TOX).
Figure 2
Figure 2. The PARP catalytic domain is highly conserved across the PARP family
(A) Alignment of the catalytic domain structures from mammalian PARP-1 (PDB 1A26; green), PARP-2 (PDB 1GSO; yellow), and PARP-3 (PDB 3FHB; blue). (B) Alignment of the catalytic domain structures from mammalian PARPs 1, 2, 3, 5a, 5b, 10, 12, 14, 15 (PDB 1A26, 1GSO, 3FHB, 2RF5, 3KR7, 3HKV, 2PQF, 3GOY, 3GEY, respectively). In (A) and (B), NAD+ has been modeled in based on a structure of diptheria toxin (PDB 1TOX).
Figure 3
Figure 3. The chromatin landscape at the promoters of highly expressed genes
Schematic of average genomic ChIP and nucleosome mapping data across the promoters of the most highly expressed genes (top quartile) in cells. The graphs are based on data from the literature: PARP- 1 and H1 (Krishnakumar et al., 2008), H3K4me3 (Barski et al., 2007), H3K9ac (Wang et al., 2008b), and nucleosome positioning (Schones et al., 2008).
Figure 4
Figure 4. Biosynthesis of NAD+ and PAR
Chemical structures of NAD+, PAR, and metabolites. The enzymes that catalyze the synthesis of NAD+ in the mammalian salvage pathway are shown. The enzymatic actions of PARP, PARG, (ADP-ribosyl) protein hydrolase, and (ADP-ribosyl) protein lyase are also indicated.
Figure 5
Figure 5. Interactions and functions of PARP-1 in the nucleus
PARP-1 interacts with and PARylates proteins involved in DNA repair, transcription, DNA methylation, and the regulation of chromatin structure and histone modification to control physiological and pathological outcomes.
Figure 6
Figure 6. Covalent post-translational modifications of PARP-1
Schematic representation of PARP-1 modifications: PARylation, phosphorylation, acetylation, SUMOylation, ubiquitylation, as described in the text.
Figure 7
Figure 7. PAR-binding motifs
(A) PAR binding motifs, as found in dHrp38, a protein that regulates alternative splicing of RNA transcripts. (B) PAR-binding zinc fingers (PBZs), as found in hAPLF, a protein involved in DNA damage checkpoints. The structures of the two PBZs from hAPLF are shown. (C) Macrodomains, as found in macroH2A1.1, a histone variant involved in setting the chromatin environment. The structure of the macrodomain of macroH2A1.1 bound to ADP-ribose is shown.
Figure 8
Figure 8
Structures of PARP inhibitors.
See this image and copyright information in PMC

"V体育ios版" References

    1. Aguilar-Quesada R, Munoz-Gamez JA, Martin-Oliva D, Peralta A, Valenzuela MT, Matinez-Romero R, Quiles-Perez R, Menissier-de Murcia J, de Murcia G, Ruiz de Almodovar M, Oliver FJ. Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition. BMC Mol Biol. 2007;8:29. - V体育安卓版 - PMC - PubMed
    1. Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, et al. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009;325:1240–1243. - PMC - PubMed
    1. Ahel I, Ahel D, Matsusaka T, Clark AJ, Pines J, Boulton SJ, West SC. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature. 2008;451:81–85. - PubMed
    1. Altmeyer M, Messner S, Hassa PO, Fey M, Hottiger MO. Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites. Nucleic Acids Res. 2009;37:3723–3738. - PMC - PubMed
    1. Alvarez-Gonzalez R, Jacobson MK. Characterization of polymers of adenosine diphosphate ribose generated in vitro and in vivo. Biochemistry. 1987;26:3218–3224. - VSports最新版本 - PubMed

Substances (VSports在线直播)