Poly(A)-specific ribonuclease explained

Poly(A)-specific ribonuclease (PARN), also known as polyadenylate-specific ribonuclease or deadenylating nuclease (DAN), is an enzyme that in humans is encoded by the PARN gene.^{[1] [2]}

Function

Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. The amino acid sequence of poly(A)-specific ribonuclease shows homology to the RNase D family of 3'-exonucleases. The protein appears to be localized in both the nucleus and the cytoplasm. It is not stably associated with polysomes or ribosomal subunits.^[2] Hereditary mutations in PARN lead to the bone marrow failure disease dyskeratosis congenita which is caused by defective telomerase RNA processing and degradation in patients.^{[3] [4] [5] [6] [7] [8] [9]}

Further reading

• Körner CG, Wahle E . Poly(A) tail shortening by a mammalian poly(A)-specific 3'-exoribonuclease . The Journal of Biological Chemistry . 272 . 16 . 10448–56 . April 1997 . 9099687 . 10.1074/jbc.272.16.10448 . free .
• Körner CG, Wormington M, Muckenthaler M, Schneider S, Dehlin E, Wahle E . The deadenylating nuclease (DAN) is involved in poly(A) tail removal during the meiotic maturation of Xenopus oocytes . The EMBO Journal . 17 . 18 . 5427–37 . September 1998 . 9736620 . 1170868 . 10.1093/emboj/17.18.5427 .
• Dehlin E, Wormington M, Körner CG, Wahle E . Cap-dependent deadenylation of mRNA . The EMBO Journal . 19 . 5 . 1079–86 . March 2000 . 10698948 . 305646 . 10.1093/emboj/19.5.1079 .
• Martinez J, Ren YG, Thuresson AC, Hellman U, Astrom J, Virtanen A . A 54-kDa fragment of the Poly(A)-specific ribonuclease is an oligomeric, processive, and cap-interacting Poly(A)-specific 3' exonuclease . The Journal of Biological Chemistry . 275 . 31 . 24222–30 . August 2000 . 10801819 . 10.1074/jbc.M001705200 . free .
• Gao M, Fritz DT, Ford LP, Wilusz J . Interaction between a poly(A)-specific ribonuclease and the 5' cap influences mRNA deadenylation rates in vitro . Molecular Cell . 5 . 3 . 479–88 . March 2000 . 10882133 . 2811581 . 10.1016/S1097-2765(00)80442-6 .
• Gao M, Wilusz CJ, Peltz SW, Wilusz J . A novel mRNA-decapping activity in HeLa cytoplasmic extracts is regulated by AU-rich elements . The EMBO Journal . 20 . 5 . 1134–43 . March 2001 . 11230136 . 145468 . 10.1093/emboj/20.5.1134 .
• Martînez J, Ren YG, Nilsson P, Ehrenberg M, Virtanen A . The mRNA cap structure stimulates rate of poly(A) removal and amplifies processivity of degradation . The Journal of Biological Chemistry . 276 . 30 . 27923–9 . July 2001 . 11359775 . 10.1074/jbc.M102270200 . free .
• Copeland PR, Wormington M . The mechanism and regulation of deadenylation: identification and characterization of Xenopus PARN . RNA . 7 . 6 . 875–86 . June 2001 . 11424938 . 1370141 . 10.1017/S1355838201010020 .
• Chen CY, Gherzi R, Ong SE, Chan EL, Raijmakers R, Pruijn GJ, Stoecklin G, Moroni C, Mann M, Karin M . AU binding proteins recruit the exosome to degrade ARE-containing mRNAs . Cell . 107 . 4 . 451–64 . November 2001 . 11719186 . 10.1016/S0092-8674(01)00578-5 . 14817671 . free .
• Ren YG, Martínez J, Virtanen A . Identification of the active site of poly(A)-specific ribonuclease by site-directed mutagenesis and Fe(2+)-mediated cleavage . The Journal of Biological Chemistry . 277 . 8 . 5982–7 . February 2002 . 11742007 . 10.1074/jbc.M111515200 . free .
• Andersen JS, Lyon CE, Fox AH, Leung AK, Lam YW, Steen H, Mann M, Lamond AI . Directed proteomic analysis of the human nucleolus . Current Biology . 12 . 1 . 1–11 . January 2002 . 11790298 . 10.1016/S0960-9822(01)00650-9 . 14132033 . free . 2002CBio...12....1A .
• Scherl A, Couté Y, Déon C, Callé A, Kindbeiter K, Sanchez JC, Greco A, Hochstrasser D, Diaz JJ . Functional proteomic analysis of human nucleolus . Molecular Biology of the Cell . 13 . 11 . 4100–9 . November 2002 . 12429849 . 133617 . 10.1091/mbc.E02-05-0271 .
• Lai WS, Kennington EA, Blackshear PJ . Tristetraprolin and its family members can promote the cell-free deadenylation of AU-rich element-containing mRNAs by poly(A) ribonuclease . Molecular and Cellular Biology . 23 . 11 . 3798–812 . June 2003 . 12748283 . 155217 . 10.1128/MCB.23.11.3798-3812.2003 .
• Lejeune F, Li X, Maquat LE . Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities . Molecular Cell . 12 . 3 . 675–87 . September 2003 . 14527413 . 10.1016/S1097-2765(03)00349-6 . free .
• Gherzi R, Lee KY, Briata P, Wegmüller D, Moroni C, Karin M, Chen CY . A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery . Molecular Cell . 14 . 5 . 571–83 . June 2004 . 15175153 . 10.1016/j.molcel.2004.05.002 . free .
• Lehner B, Sanderson CM . A protein interaction framework for human mRNA degradation . Genome Research . 14 . 7 . 1315–23 . July 2004 . 15231747 . 442147 . 10.1101/gr.2122004 .
• Ren YG, Kirsebom LA, Virtanen A . Coordination of divalent metal ions in the active site of poly(A)-specific ribonuclease . The Journal of Biological Chemistry . 279 . 47 . 48702–6 . November 2004 . 15358788 . 10.1074/jbc.M403858200 . free.

Notes and References

1. Buiting K, Körner C, Ulrich B, Wahle E, Horsthemke B . The human gene for the poly(A)-specific ribonuclease (PARN) maps to 16p13 and has a truncated copy in the Prader-Willi/Angelman region on 15q11→q13 . Cytogenetics and Cell Genetics . 87 . 1–2 . 125–31 . May 2000 . 10640832 . 10.1159/000015378 . 28498478 .
2. Web site: Entrez Gene: PARN poly(A)-specific ribonuclease (deadenylation nuclease).
3. Tummala H, Walne A, Collopy L, Cardoso S, de la Fuente J, Lawson S, Powell J, Cooper N, Foster A, Mohammed S, Plagnol V, Vulliamy T, Dokal I . Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita . The Journal of Clinical Investigation . 125 . 5 . 2151–60 . May 2015 . 25893599 . 4463202 . 10.1172/JCI78963 .
4. Dhanraj S, Gunja SM, Deveau AP, Nissbeck M, Boonyawat B, Coombs AJ, Renieri A, Mucciolo M, Marozza A, Buoni S, Turner L, Li H, Jarrar A, Sabanayagam M, Kirby M, Shago M, Pinto D, Berman JN, Scherer SW, Virtanen A, Dror Y . Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN) . Journal of Medical Genetics . 52 . 11 . 738–48 . November 2015 . 26342108 . 10.1136/jmedgenet-2015-103292 . 19822046 .
5. Stuart BD, Choi J, Zaidi S, Xing C, Holohan B, Chen R, Choi M, Dharwadkar P, Torres F, Girod CE, Weissler J, Fitzgerald J, Kershaw C, Klesney-Tait J, Mageto Y, Shay JW, Ji W, Bilguvar K, Mane S, Lifton RP, Garcia CK . Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening . Nature Genetics . 47 . 5 . 512–7 . May 2015 . 25848748 . 4414891 . 10.1038/ng.3278 .
6. Shukla S, Schmidt JC, Goldfarb KC, Cech TR, Parker R . Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects . Nature Structural & Molecular Biology . 23 . 4 . 286–92 . April 2016 . 26950371 . 4830462 . 10.1038/nsmb.3184 .
7. Tseng CK, Wang HF, Burns AM, Schroeder MR, Gaspari M, Baumann P . Human Telomerase RNA Processing and Quality Control . Cell Reports . 13 . 10 . 2232–43 . December 2015 . 26628367 . 10.1016/j.celrep.2015.10.075 . free .
8. Nguyen D, Grenier St-Sauveur V, Bergeron D, Dupuis-Sandoval F, Scott MS, Bachand F . A Polyadenylation-Dependent 3' End Maturation Pathway Is Required for the Synthesis of the Human Telomerase RNA . Cell Reports . 13 . 10 . 2244–57 . December 2015 . 26628368 . 10.1016/j.celrep.2015.11.003 . free .
9. Moon DH, Segal M, Boyraz B, Guinan E, Hofmann I, Cahan P, Tai AK, Agarwal S . Poly(A)-specific ribonuclease (PARN) mediates 3'-end maturation of the telomerase RNA component . Nature Genetics . 47 . 12 . 1482–8 . December 2015 . 26482878 . 4791094 . 10.1038/ng.3423 .