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Poly [ADP-ribose] polymerase 1

Definition:

Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair. Mediates glutamate, aspartate, serine, histidine or tyrosine ADP-ribosylation of proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of target residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Specificity for the different amino acids is conferred by interacting factors, such as HPF1 and NMNAT1. Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 confers serine specificity by completing the PARP1 active site. Also catalyzes tyrosine ADP-ribosylation of target proteins following interaction with HPF1. Following interaction with NMNAT1, catalyzes glutamate and aspartate ADP-ribosylation of target proteins; NMNAT1 confers glutamate and aspartate specificity (By similarity). PARP1 initiates the repair of DNA breaks: recognizes and binds DNA breaks within chromatin and recruits HPF1, licensing serine ADP-ribosylation of target proteins, such as histones (H2BS6ADPr and H3S10ADPr), thereby promoting decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks. HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP1 in order to limit the length of poly-ADP-ribose chains. In addition to base excision repair (BER) pathway, also involved in double-strand breaks (DSBs) repair: together with TIMELESS, accumulates at DNA damage sites and promotes homologous recombination repair by mediating poly-ADP-ribosylation. Mediates the poly-ADP-ribosylation of a number of proteins, including itself, APLF, CHFR and NFAT5. In addition to proteins, also able to ADP-ribosylate DNA: catalyzes ADP-ribosylation of DNA strand break termini containing terminal phosphates and a 2'-OH group in single- and double-stranded DNA, respectively. Required for PARP9 and DTX3L recruitment to DNA damage sites. PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. PARP1-mediated DNA repair in neurons plays a role in sleep: senses DNA damage in neurons and promotes sleep, facilitating efficient DNA repair (By similarity). In addition to DNA repair, also involved in other processes, such as transcription regulation, programmed cell death, membrane repair, adipogenesis and innate immunity. Acts as a repressor of transcription: binds to nucleosomes and modulates chromatin structure in a manner similar to histone H1, thereby altering RNA polymerase II. Acts both as a positive and negative regulator of transcription elongation, depending on the context. Acts as a positive regulator of transcription elongation by mediating poly-ADP-ribosylation of NELFE, preventing RNA-binding activity of NELFE and relieving transcription pausing. Acts as a negative regulator of transcription elongation in response to DNA damage by catalyzing poly-ADP-ribosylation of CCNT1, disrupting the phase separation activity of CCNT1 and subsequent activation of CDK9. Involved in replication fork progression following interaction with CARM1: mediates poly-ADP-ribosylation at replication forks, slowing fork progression. Poly-ADP-ribose chains generated by PARP1 also play a role in poly-ADP-ribose-dependent cell death, a process named parthanatos (By similarity). Also acts as a negative regulator of the cGAS-STING pathway. Acts by mediating poly-ADP-ribosylation of CGAS: PARP1 translocates into the cytosol following phosphorylation by PRKDC and catalyzes poly-ADP-ribosylation and inactivation of CGAS. Acts as a negative regulator of adipogenesis: catalyzes poly-ADP-ribosylation of histone H2B on 'Glu-35' (H2BE35ADPr) following interaction with NMNAT1, inhibiting phosphorylation of H2B at 'Ser-36' (H2BS36ph), thereby blocking expression of pro-adipogenetic genes (By similarity). Involved in the synthesis of ATP in the nucleus, together with NMNAT1, PARG and NUDT5. Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming.; [Poly [ADP-ribose] polymerase 1, processed C-terminus]: Promotes AIFM1-mediated apoptosis. This form, which translocates into the cytoplasm following cleavage by caspase-3 (CASP3) and caspase-7 (CASP7) in response to apoptosis, is auto-poly-ADP-ribosylated and serves as a poly-ADP-ribose carrier to induce AIFM1-mediated apoptosis.; [Poly [ADP-ribose] polymerase 1, processed N-terminus]: This cleavage form irreversibly binds to DNA breaks and interferes with DNA repair, promoting DNA damage-induced apoptosis.

References:

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[16]. Byeong Jin Ye, et al. PARP1-mediated PARylation of TonEBP prevents R-loop-associated DNA damage. DNA Repair (Amst). 2021 Aug;104:103132. [Content Brief]

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[18]. Marcin J Suskiewicz, et al. HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation. Nature. 2020 Mar;579(7800):598-602. [Content Brief]

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[20]. Fa-Hui Sun, et al. HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones. Nat Commun. 2021 Feb 15;12(1):1028. [Content Brief]

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[25]. Dragana Ahel, et al. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009 Sep 4;325(5945):1240-3. [Content Brief]

[26]. Johannes Rudolph, et al. HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase. Elife. 2021 Mar 8;10:e65773. [Content Brief]

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[28]. Sebastian Eustermann, et al. Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1. Mol Cell. 2015 Dec 3;60(5):742-754. [Content Brief]

[29]. Deena M Leslie Pedrioli, et al. Comprehensive ADP-ribosylome analysis identifies tyrosine as an ADP-ribose acceptor site. EMBO Rep. 2018 Aug;19(8):e45310. [Content Brief]

[30]. Ian Gibbs-Seymour, et al. HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity. Mol Cell. 2016 May 5;62(3):432-442. [Content Brief]

[31]. Bryan A Gibson, et al. Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science. 2016 Jul 1;353(6294):45-50. [Content Brief]

[32]. Masato Mashimo, et al. PARP1 is activated by membrane damage and is involved in membrane repair through poly(ADP-ribosyl)ation. Genes Cells. 2022 Apr;27(4):305-312. [Content Brief]

[33]. Mi Young Kim, et al. NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1. Cell. 2004 Dec 17;119(6):803-14. [Content Brief]

[34]. Masato Mashimo, et al. The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis. J Biol Chem. 2021 Jan-Jun;296:100046. [Content Brief]

[35]. Süheda Erener, et al. Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-κB target genes. Mol Cell. 2012 Apr 27;46(2):200-11. [Content Brief]

[36]. Ibtissam Talhaoui, et al. Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragments in vitro. Nucleic Acids Res. 2016 Nov 2;44(19):9279-9295. [Content Brief]

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[38]. Fei Wang, et al. Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS. Mol Cell. 2022 Jun 2;82(11):2032-2049.e7. [Content Brief]

[39]. Shin-ichiro Kanno, et al. A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses. EMBO J. 2007 Apr 18;26(8):2094-103. [Content Brief]

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[41]. Huanyi Fu, et al. Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage. Nat Cell Biol. 2022 Apr;24(4):513-525. [Content Brief]

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[43]. V Rolli, et al. Random mutagenesis of the poly(ADP-ribose) polymerase catalytic domain reveals amino acids involved in polymer branching. Biochemistry. 1997 Oct 7;36(40):12147-54. [Content Brief]

[44]. Marie-France Langelier, et al. A third zinc-binding domain of human poly(ADP-ribose) polymerase-1 coordinates DNA-dependent enzyme activation. J Biol Chem. 2008 Feb 15;283(7):4105-14. [Content Brief]

[45]. Emma Bolderson, et al. Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage. Nat Commun. 2019 Dec 3;10(1):5501. [Content Brief]

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[47]. Qingsheng Yan, et al. BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8. Mol Cell Biol. 2013 Feb;33(4):845-57. [Content Brief]

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