Poly (ADP-ribose) polymerase

From Proteopedia

Contents 1 Function 2 Relevance 3 Structural highlights 4 3D Structures of Poly (ADP-ribose) polymerase Function Poly (ADP-ribose) polymerase (PARP) is involved in DNA repair and programmed cell death. The PARP family contains 17 members. PARP-1 and PARP-2 recognize and is activated by DNA breaks[1], [2]. PARP-3 prevents from extensive end resection to promote double-strand DNA repair [3]. PARP-10 inhibits Myc transformation[4]. It contains a RNA recognition motif (RRM). PARP-12 has roles in viral immunity and microRNA-mediated stress responses [5]. PARP-14 promotes the survival of myeloma cells by binding and inhibiting JNK1 [6]. Tankyrase (Tank1 and Tank2) are PARPs which regulate telomere length[7]. Tank contains ankyrin repeats (a 33-residue repeat with 2 α-helices separated by loops). Relevance PARP inhibitors are investigated as mono therapy against breast cancer[8]. Olaparib is a PARP inhibitor used as medication against ovarian cancer. Over-expression of PARP-14 rescues myeloma cells from apoptosis. Structural highlights PARP1 is composed of 3 domains. Among them are the N terminal DNA-binding domain which contains 5 zinc fingers (residues 1-97, 105-206, 207-366). The auto modification (AD) domain which contains a breast cancer 1 protein (BRCT) C-terminus domain (residues 386-485) and a WGR domain (rich in Trp, Gly and Arg) (residues 517-642). The C terminal domain which includes the catalytic domain (or PARP domain) (residues 662-1011)[9]. A potential drug binds at the active site pocket[10]. 3D Structures of Poly (ADP-ribose) polymerase Poly(ADP-ribose) polymerase 3D structures

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References

1. ↑ Shall S, de Murcia G. Poly(ADP-ribose) polymerase-1: what have we learned from the deficient mouse model? Mutat Res. 2000 Jun 30;460(1):1-15. PMID:10856830
2. ↑ Dantzer F, Giraud-Panis MJ, Jaco I, Ame JC, Schultz I, Blasco M, Koering CE, Gilson E, Menissier-de Murcia J, de Murcia G, Schreiber V. Functional interaction between poly(ADP-Ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2. Mol Cell Biol. 2004 Feb;24(4):1595-607. PMID:14749375
3. ↑ Beck C, Robert I, Reina-San-Martin B, Schreiber V, Dantzer F. Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp Cell Res. 2014 Nov 15;329(1):18-25. doi: 10.1016/j.yexcr.2014.07.003. Epub, 2014 Jul 10. PMID:25017100 doi:http://dx.doi.org/10.1016/j.yexcr.2014.07.003
4. ↑ Yu M, Schreek S, Cerni C, Schamberger C, Lesniewicz K, Poreba E, Vervoorts J, Walsemann G, Grotzinger J, Kremmer E, Mehraein Y, Mertsching J, Kraft R, Austen M, Luscher-Firzlaff J, Luscher B. PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. Oncogene. 2005 Mar 17;24(12):1982-93. PMID:15674325 doi:http://dx.doi.org/1208410
5. ↑ Karlberg T, Klepsch M, Thorsell AG, Andersson CD, Linusson A, Schuler H. Structural Basis for Lack of ADP-Ribosyltransferase Activity in Poly(ADP-Ribose) Polymerase-13/Zinc Finger Antiviral Protein. J Biol Chem. 2015 Jan 29. pii: jbc.M114.630160. PMID:25635049 doi:http://dx.doi.org/10.1074/jbc.M114.630160
6. ↑ Barbarulo A, Iansante V, Chaidos A, Naresh K, Rahemtulla A, Franzoso G, Karadimitris A, Haskard DO, Papa S, Bubici C. Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma. Oncogene. 2013 Sep 5;32(36):4231-42. doi: 10.1038/onc.2012.448. Epub 2012 Oct 8. PMID:23045269 doi:http://dx.doi.org/10.1038/onc.2012.448
7. ↑ Cook BD, Dynek JN, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol. 2002 Jan;22(1):332-42. PMID:11739745
8. ↑ Rios J, Puhalla S. PARP inhibitors in breast cancer: BRCA and beyond. Oncology (Williston Park). 2011 Oct;25(11):1014-25. PMID:22106552
9. ↑ 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 Jun;37(11):3723-38. doi: 10.1093/nar/gkp229. Epub 2009, Apr 16. PMID:19372272 doi:http://dx.doi.org/10.1093/nar/gkp229
10. ↑ Patel MR, Bhatt A, Steffen JD, Chergui A, Murai J, Pommier Y, Pascal JM, Trombetta LD, Fronczek FR, Talele TT. Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors. J Med Chem. 2014 Jun 25. PMID:24922587 doi:http://dx.doi.org/10.1021/jm5002502