Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality

IScience
Paola SaneseCristiano Simone

Abstract

SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.

References

Oct 29, 1999·Genes & Development·A J PierceM Jasin
Jan 31, 2003·Nature·Christopher J Bakkenist, Michael B Kastan
Mar 4, 2003·Nature Reviews. Cancer·Yosef Shiloh
Jul 6, 2004·Nature Cell Biology·Ryuji HamamotoYusuke Nakamura
Jul 21, 2004·Bioinformatics·David J Reiss, Benno Schwikowski
Nov 19, 2004·Nature·Charles Sawyers
Jan 31, 2006·Cancer Science·Ryuji HamamotoYoichi Furukawa
Aug 9, 2006·Nature Clinical Practice. Oncology·I Bernard Weinstein, Andrew K Joe
Oct 24, 2007·Nature Cell Biology·Zhongsheng YouTony Hunter
Dec 28, 2007·Cell·Hiroyuki TakaiTitia de Lange
Mar 24, 2009·Cell·Aura CarreiraStephen C Kowalczykowski
Jun 11, 2009·The Journal of Biological Chemistry·Hyunjung KimWoojin An
Jul 14, 2009·Peptides·Anthony KusalikDarja Kanduc
Oct 3, 2009·Protein Science : a Publication of the Protein Society·Fabien KiekenPaul L Sorgen
Mar 11, 2010·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Nancie PetrucelliGerald L Feldman
Jul 7, 2011·Nature Structural & Molecular Biology·William K Holloman
Nov 3, 2011·Current Protein & Peptide Science·Maria V SudnitsynaNikolai B Gusev
Dec 24, 2011·Cancer Research·Alicia M Cock-RadaJonathan B Weitzman
Apr 3, 2012·Nucleic Acids Research·Lumir KrejciXiaolan Zhao
Sep 4, 2012·Methods in Molecular Biology·Amanda Gunn, Jeremy M Stark
Jan 30, 2013·Molecular and Cellular Biology·Akiyuki Nishimura, Maurine E Linder
Apr 4, 2013·Science Signaling·Jianjiong GaoNikolaus Schultz
Sep 5, 2013·Cold Spring Harbor Perspectives in Biology·Alexandre Maréchal, Lee Zou
Dec 12, 2013·Nature Reviews. Molecular Cell Biology·Stephanie Panier, Simon J Boulton
May 23, 2014·Nature·Pawel K MazurOr Gozani
Mar 3, 2015·Journal of Cellular Physiology·Alessia PesericoCristiano Simone
Mar 31, 2015·Journal of Plant Physiology·Amr R A KatayaCathrine Lillo
Apr 17, 2016·Nucleic Acids Research·Gouri ChatterjeeRyan B Jensen
Sep 15, 2016·Oncotarget·Yuichiro YoshiokaRyuji Hamamoto
Jun 21, 2017·Scientific Reports·Yun-Ju ChenShu-Chun Teng
Aug 7, 2017·Journal of Genetic Counseling·Kathryn M BuchtelScott M Weissman

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Citations

Jun 3, 2021·Cells·Raffaella FittipaldiGiuseppina Caretti
Jul 3, 2021·International Journal of Molecular Sciences·Martina Lepore SignorileGiuseppe Ingravallo

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Methods Mentioned

BETA
surface plasmon resonance
pull-down
Co-immunoprecipitation
coIP
RNA-seq
Co-immunoprecipitation assay
transfection
immunoprecipitation
ChIP
flow cytometry

Software Mentioned

DISCOVER

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