The Histone Methyltransferase SMYD2 Methylates PARP1 and Promotes Poly(ADP-ribosyl)ation Activity in Cancer Cells

• Published in: Neoplasia (New York, N.Y.) Vol. 16; no. 3; pp. 257 - 264.e2
• Main Authors: Piao, Lianhua, Kang, Daechun, Suzuki, Takehiro, Masuda, Akiko, Dohmae, Naoshi, Nakamura, Yusuke, Hamamoto, Ryuji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2014; Elsevier
• Subjects: Amino Acid Sequence; DNA Damage - drug effects; HeLa Cells - drug effects; Histone-Lysine N-Methyltransferase - metabolism; Humans; Hydrogen Peroxide - pharmacology; Lysine - metabolism; Methylation; Molecular Sequence Data; Oncology; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose - metabolism; Poly(ADP-ribose) Polymerases - metabolism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1016/j.neo.2014.03.002

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.