ADP-ribosylhydrolase ARH3

Definition:

ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1'' position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose. Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds. Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos. Also hydrolyzes free poly(ADP-ribose) in mitochondria. Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins. Specifically degrades 1''-O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers.

References:

[1]. Pietro Fontana, et al. Serine ADP-ribosylation reversal by the hydrolase ARH3. Elife. 2017 Jun 26;6:e28533. [Content Brief]

[2]. Luca Palazzo, et al. Serine is the major residue for ADP-ribosylation upon DNA damage. Elife. 2018 Feb 26;7:e34334. [Content Brief]

[3]. Jeannette Abplanalp, et al. Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase. Nat Commun. 2017 Dec 12;8(1):2055. [Content Brief]

[4]. Atsushi Kasamatsu, et al. Hydrolysis of O-acetyl-ADP-ribose isomers by ADP-ribosylhydrolase 3. J Biol Chem. 2011 Jun 17;286(24):21110-7. [Content Brief]

[5]. Ivo A Hendriks, et al. The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome. Nat Commun. 2021 Oct 8;12(1):5893. [Content Brief]

[6]. Masato Mashimo, et al. PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells. JCI Insight. 2019 Feb 21;4(4):e124519. [Content Brief]

[7]. Juan José Bonfiglio, et al. An HPF1/PARP1-Based Chemical Biology Strategy for Exploring ADP-Ribosylation. Cell. 2020 Nov 12;183(4):1086-1102.e23. [Content Brief]

[8]. Shunya Oka, et al. Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase. J Biol Chem. 2006 Jan 13;281(2):705-13. [Content Brief]

[9]. Johannes Gregor Matthias Rack, et al. Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal. Nat Commun. 2021 Jul 28;12(1):4581. [Content Brief]

[10]. Evgeniia Prokhorova, et al. Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. Mol Cell. 2021 Jun 17;81(12):2640-2655.e8. [Content Brief]

[11]. Mengxi Wang, et al. Structure-function analyses reveal the mechanism of the ARH3-dependent hydrolysis of ADP-ribosylation. J Biol Chem. 2018 Sep 14;293(37):14470-14480. [Content Brief]

[12]. Danique Beijer, et al. Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response. Life Sci Alliance. 2021 Sep 3;4(11):e202101057. [Content Brief]

[13]. Katharina Danhauser, et al. Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. Am J Hum Genet. 2018 Nov 1;103(5):817-825. [Content Brief]

[14]. Jim Voorneveld, et al. Molecular Tools for the Study of ADP-Ribosylation: A Unified and Versatile Method to Synthesise Native Mono-ADP-Ribosylated Peptides. Chemistry. 2021 Jul 21;27(41):10621-10627. [Content Brief]

[15]. Tohru Ono, et al. The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylases. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16687-91. [Content Brief]

[16]. Yasin Pourfarjam, et al. Structure of human ADP-ribosyl-acceptor hydrolase 3 bound to ADP-ribose reveals a conformational switch that enables specific substrate recognition. J Biol Chem. 2018 Aug 10;293(32):12350-12359. [Content Brief]

[17]. Yasin Pourfarjam, et al. Structural and biochemical analysis of human ADP-ribosyl-acceptor hydrolase 3 reveals the basis of metal selectivity and different roles for the two magnesium ions. J Biol Chem. 2021 Jan-Jun;296:100692. [Content Brief]

[18]. Marc Niere, et al. ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose). J Biol Chem. 2012 May 11;287(20):16088-102. [Content Brief]

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