title: The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells.
abstract: Poly(ADP-ribose) polymerase-1 (PARP1) catalyzes the poly(ADP-ribosyl)ation of protein acceptors using NAD(+) as the substrate is now considered as an important target for development of anticancer therapy. PARP1 is known to be post-translationally modified in various ways including phosphorylation and ubiquitination, but the physiological role of PARP1 methylation is not well understood. Herein we demonstrated that the histone methyltransferase SMYD2, which plays critical roles in human carcinogenesis, mono-methylated PARP1. We confirmed lysine 528 to be a target of SMYD2-dependent PARP1 methylation by LC-MS/MS and Edman Degradation analyses. Importantly, methylated PARP1 revealed enhanced poly(ADP-ribose) formation after oxidative stress, and positively regulated the poly(ADP-ribosyl)ation activity of PARP1. Hence, our study unveils a novel mechanism of PARP1 in human cancer through its methylation by SMYD2.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL 60637, USA.
authors.forename: Lianhua
authors.initials: L
authors.lastname: Piao
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Daechun
authors.initials: D
authors.lastname: Kang
authors.affiliation: Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Dohmae
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL 60637, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL 60637, USA; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: rhamamoto@medicine.bsd.uchicago.edu.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D000595:Amino Acid Sequence; D004249:DNA Damage / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008969:Molecular Sequence Data; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D011064:Poly Adenosine Diphosphate Ribose; D006861:Hydrogen Peroxide; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008239:Lysine
references.citation: J Pathol. 2005 Jan;205(2):275-92
references.pmid: 15641020
references.citation: J Biol Chem. 2005 Dec 9;280(49):40450-64
references.pmid: 16204234
references.citation: Nucleic Acids Res. 2009 Jun;37(11):3723-38
references.pmid: 19372272
references.citation: Nature. 2012 Dec 6;492(7427):108-12
references.pmid: 23051747
references.citation: Nature. 2006 Nov 30;444(7119):629-32
references.pmid: 17108971
references.citation: Carcinogenesis. 2009 Jul;30(7):1139-46
references.pmid: 19423649
references.citation: Biochim Biophys Acta. 1999 Feb 10;1430(1):119-26
references.pmid: 10082940
references.citation: Carcinogenesis. 2009 Jan;30(1):2-10
references.pmid: 18978338
references.citation: Expert Rev Anticancer Ther. 2010 Jul;10(7):1125-36
references.pmid: 20645701
references.citation: Nature. 1980 Feb 7;283(5747):593-6
references.pmid: 6243744
references.citation: Mol Cancer Ther. 2005 Sep;4(9):1364-8
references.pmid: 16170028
references.citation: Nat Commun. 2012;3:1072
references.pmid: 22990868
references.citation: Neoplasia. 2012 Jun;14(6):476-86
references.pmid: 22787429
references.citation: Structure. 2011 Sep 7;19(9):1262-73
references.pmid: 21782458
references.citation: Cancer Res. 2011 Sep 1;71(17):5626-34
references.pmid: 21795476
references.citation: Br J Cancer. 2011 Mar 1;104(5):750-5
references.pmid: 21326243
references.citation: Anal Bioanal Chem. 2013 Oct;405(25):8073-81
references.pmid: 23719935
references.citation: J Mol Biol. 2006 Feb 17;356(2):257-65
references.pmid: 16364363
references.citation: Biosci Trends. 2011 Dec;5(6):231-8
references.pmid: 22281536
references.citation: Cell Res. 2011 Mar;21(3):502-17
references.pmid: 21321605
references.citation: J Biol Chem. 1981 May 10;256(9):4135-7
references.pmid: 6260786
references.citation: Front Med. 2012 Jun;6(2):156-64
references.pmid: 22660976
references.citation: Neoplasia. 2011 Oct;13(10):887-98
references.pmid: 22028615
references.citation: J Biol Chem. 1984 Apr 25;259(8):4770-6
references.pmid: 6325408
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3664-9
references.pmid: 18559580
references.citation: BMC Med. 2012 Mar 09;10:25
references.pmid: 22401667
references.citation: Curr Med Chem. 2003 Feb;10(4):321-40
references.pmid: 12570705
references.citation: Clin Cancer Res. 2008 Dec 1;14(23):7917-23
references.pmid: 19047122
references.citation: Nat Chem Biol. 2012 Nov;8(11):890-6
references.pmid: 23023262
references.citation: Nat Cell Biol. 2004 Aug;6(8):731-40
references.pmid: 15235609
references.citation: Genes Chromosomes Cancer. 2011 Jan;50(1):13-24
references.pmid: 20931645
references.citation: Ann Oncol. 2012 May;23(5):1156-1164
references.pmid: 21908496
references.citation: Cancer Sci. 2006 Feb;97(2):113-8
references.pmid: 16441421
references.citation: EMBO J. 2009 Nov 18;28(22):3534-48
references.pmid: 19779455
references.citation: J Biol Chem. 2004 Dec 31;279(53):55117-26
references.pmid: 15498778
references.citation: J Proteome Res. 2009 Feb;8(2):1014-29
references.pmid: 19105632
references.citation: Lancet. 2010 Jul 24;376(9737):245-51
references.pmid: 20609468
references.citation: Int J Cancer. 2004 Oct 10;111(6):813-8
references.pmid: 15300792
references.citation: Nucleic Acids Res. 2006;34(21):6170-82
references.pmid: 17088286
references.citation: Nature. 2001 May 17;411(6835):366-74
references.pmid: 11357144
references.citation: Mol Cancer. 2006 Jun 28;5:26
references.pmid: 16805913
references.citation: Cancer Sci. 2011 Jul;102(7):1298-305
references.pmid: 21539681
references.citation: Biochemistry. 2000 Jun 27;39(25):7559-69
references.pmid: 10858306
references.citation: Cancer Res. 2012 Jul 1;72(13):3217-27
references.pmid: 22556262
references.citation: Int J Cancer. 2011 Feb 1;128(3):574-86
references.pmid: 20333681
references.citation: Trends Biochem Sci. 1994 Apr;19(4):172-6
references.pmid: 8016868
references.citation: J Cell Biochem. 2008 May 1;104(1):318-28
references.pmid: 18041763
references.citation: Clin Cancer Res. 2003 Nov 1;9(14):5370-9
references.pmid: 14614022
references.citation: Mol Cell Proteomics. 2008 Mar;7(3):560-72
references.pmid: 18065756
references.citation: Clin Transl Oncol. 2008 Jun;10(6):318-23
references.pmid: 18558578