ADP-ribosylhydrolase 3 explained

(ADP-ribosyl)hydrolase 3 (ARH3) is an enzyme that in humans is encoded by the ADPRHL2 gene (also called ADPRS^[1]).^{[2] [3] [4]} This enzyme reverses the proteins’ post-translational addition of ADP-ribose to serine residues as part of the DNA damage response^{[5] [6]} The enzyme is also known to cleave poly(ADP-ribose) polymers, 1''-O-acetyl-ADP-ribose and alpha-NAD^{+[7] [8] [9]}

Role in disease

Loss-of-function mutations in the ADPRHL2 gene result in a recently defined disorder called stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS; OMIM: 618170).^{[10] [11] [12] [13] [14]} The CONDSIAS is an autosomal recessive disorder which its pertinent gene (ADPRHL2) is mapped on chromosome 1p35.3-p34.1. The phenotypes of this disorder have been reported as neurodegeneration, variable ataxia and seizures, tremor, nystagmus, balance problems, cerebellar, spinal cord and cerebral atrophy, hearing impairment and occasionally hearing loss, ptosis, ophthalmoplegia, dysarthria, muscle weakness, axonal neuropathy, dysmetria, and tongue fasciculation. Symptoms and severity of the disorder appear to be different in patients and sometimes lead to early childhood death. In other words, although older patients present most of the above-mentioned symptoms, younger patients experience loss of developmental milestones and death in their early infancy.^[15]

See also

• ADP-ribosylhydrolase

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Kernstock S, Koch-Nolte F, Mueller-Dieckmann J, Weiss MS, Mueller-Dieckmann C . Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of human ARH3, the first eukaryotic protein-ADP-ribosylhydrolase . Acta Crystallographica. Section F, Structural Biology and Crystallization Communications . 62 . Pt 3 . 224–7 . March 2006 . 16511307 . 2197168 . 10.1107/S1744309106003435 .
• Mueller-Dieckmann C, Kernstock S, Lisurek M, von Kries JP, Haag F, Weiss MS, Koch-Nolte F . The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights into the reversibility of protein ADP-ribosylation . Proceedings of the National Academy of Sciences of the United States of America . 103 . 41 . 15026–31 . October 2006 . 17015823 . 1622773 . 10.1073/pnas.0606762103 . 2006PNAS..10315026M . free .
• Ono T, Kasamatsu A, Oka S, Moss J . The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylases . Proceedings of the National Academy of Sciences of the United States of America . 103 . 45 . 16687–91 . November 2006 . 17075046 . 1636516 . 10.1073/pnas.0607911103 . 2006PNAS..10316687O . free .

Notes and References

1. Web site: Gene symbol report | HUGO Gene Nomenclature Committee.
2. Glowacki G, Braren R, Firner K, Nissen M, Kühl M, Reche P, Bazan F, Cetkovic-Cvrlje M, Leiter E, Haag F, Koch-Nolte F . 6 . The family of toxin-related ecto-ADP-ribosyltransferases in humans and the mouse . Protein Science . 11 . 7 . 1657–70 . July 2002 . 12070318 . 2373659 . 10.1110/ps.0200602 .
3. Oka S, Kato J, Moss J . Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase . The Journal of Biological Chemistry . 281 . 2 . 705–13 . January 2006 . 16278211 . 10.1074/jbc.M510290200 . free .
4. Web site: Entrez Gene: ADPRHL2 ADP-ribosylhydrolase like 2.
5. Fontana P, Bonfiglio JJ, Palazzo L, Bartlett E, Matic I, Ahel I . Serine ADP-ribosylation reversal by the hydrolase ARH3 . eLife . 6 . June 2017 . 28650317 . 5552275 . 10.7554/eLife.28533 . free .
6. Rack JG, Palazzo L, Ahel I . (ADP-ribosyl)hydrolases: structure, function, and biology . Genes & Development . 34 . 5–6 . 263–284 . March 2020 . 32029451 . 7050489 . 10.1101/gad.334631.119 .
7. Stevens LA, Kato J, Kasamatsu A, Oda H, Lee DY, Moss J . The ARH and Macrodomain Families of α-ADP-ribose-acceptor Hydrolases Catalyze α-NAD⁺ Hydrolysis . ACS Chemical Biology . 14 . 12 . 2576–2584 . December 2019 . 31599159 . 10.1021/acschembio.9b00429 . 8388552 .
8. Ono T, Kasamatsu A, Oka S, Moss J . The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylases . Proceedings of the National Academy of Sciences of the United States of America . 103 . 45 . 16687–91 . November 2006 . 17075046 . 1636516 . 10.1073/pnas.0607911103 . 2006PNAS..10316687O . free .
9. Rack JG, Liu Q, Zorzini V, Voorneveld J, Ariza A, Honarmand Ebrahimi K, Reber JM, Krassnig SC, Ahel D, van der Marel GA, Mangerich A, McCullagh JS, Filippov DV, Ahel I . 6 . Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal . Nature Communications . 12 . 1 . 4581 . July 2021 . 34321462 . 10.1038/s41467-021-24723-3 . 8319183 . 2021NatCo..12.4581R .
10. Ghosh SG, Becker K, Huang H, Dixon-Salazar T, Chai G, Salpietro V, Al-Gazali L, Waisfisz Q, Wang H, Vaux KK, Stanley V, Manole A, Akpulat U, Weiss MM, Efthymiou S, Hanna MG, Minetti C, Striano P, Pisciotta L, De Grandis E, Altmüller J, Nürnberg P, Thiele H, Yis U, Okur TD, Polat AI, Amiri N, Doosti M, Karimani EG, Toosi MB, Haddad G, Karakaya M, Wirth B, van Hagen JM, Wolf NI, Maroofian R, Houlden H, Cirak S, Gleeson JG . 6 . Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome . American Journal of Human Genetics . 103 . 3 . 431–439 . September 2018 . 30100084 . 6128219 . 10.1016/j.ajhg.2018.07.010 .
11. Danhauser K, Alhaddad B, Makowski C, Piekutowska-Abramczuk D, Syrbe S, Gomez-Ospina N, Manning MA, Kostera-Pruszczyk A, Krahn-Peper C, Berutti R, Kovács-Nagy R, Gusic M, Graf E, Laugwitz L, Röblitz M, Wroblewski A, Hartmann H, Das AM, Bültmann E, Fang F, Xu M, Schatz UA, Karall D, Zellner H, Haberlandt E, Feichtinger RG, Mayr JA, Meitinger T, Prokisch H, Strom TM, Płoski R, Hoffmann GF, Pronicki M, Bonnen PE, Morlot S, Haack TB . 6 . Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy . American Journal of Human Genetics . 103 . 5 . 817–825 . November 2018 . 30401461 . 6218634 . 10.1016/j.ajhg.2018.10.005 .
12. Beijer D, Agnew T, Rack JG, Prokhorova E, Deconinck T, Ceulemans B, Peric S, Milic Rasic V, De Jonghe P, Ahel I, Baets J . 6 . Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response . Life Science Alliance . 4 . 11 . e202101057 . November 2021 . 34479984 . 8424258 . 10.26508/lsa.202101057 .
13. Mishra B, Fatima S, Agarwal A, Radhakrishnan DM, Garg A, Srivastava AK . Dystonia and Myelopathy in a Case of Stress-Induced Childhood-Onset Neurodegeneration with Ataxia and Seizures (CONDSIAS) . Movement Disorders Clinical Practice . 8 . 1 . 156–158 . January 2021 . 33426173 . 7780941 . 10.1002/mdc3.13125 .
14. Hanzlikova H, Prokhorova E, Krejcikova K, Cihlarova Z, Kalasova I, Kubovciak J, Sachova J, Hailstone R, Brazina J, Ghosh S, Cirak S, Gleeson JG, Ahel I, Caldecott KW . 6 . Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair . Nature Communications . 11 . 1 . 3391 . July 2020 . 32636369 . 7341855 . 10.1038/s41467-020-17069-9 . 2020NatCo..11.3391H .
15. Aryan H, Razmara E, Farhud D, Zarif-Yeganeh M, Zokaei S, Hassani SA, Ashrafi MR, Garshasbi M, Tavasoli AR . 6 . Novel imaging and clinical phenotypes of CONDSIAS disorder caused by a homozygous frameshift variant of ADPRHL2: a case report . BMC Neurology . 20 . 1 . 291 . August 2020 . 32746785 . 7397971 . 10.1186/s12883-020-01873-3 . free .