title: Gold nanoparticles as a platform for creating a multivalent poly-SUMO chain inhibitor that also augments ionizing radiation.
abstract: Protein-protein interactions mediated by ubiquitin-like (Ubl) modifications occur as mono-Ubl or poly-Ubl chains. Proteins that regulate poly-SUMO (small ubiquitin-like modifier) chain conjugates play important roles in cellular response to DNA damage, such as those caused by cancer radiation therapy. Additionally, high atomic number metals, such as gold, preferentially absorb much more X-ray energy than soft tissues, and thus augment the effect of ionizing radiation when delivered to cells. In this study, we demonstrate that conjugation of a weak SUMO-2/3 ligand to gold nanoparticles facilitated selective multivalent interactions with poly-SUMO-2/3 chains leading to efficient inhibition of poly-SUMO-chain-mediated protein-protein interactions. The ligand-gold particle conjugate significantly sensitized cancer cells to radiation but was not toxic to normal cells. This study demonstrates a viable approach for selective targeting of poly-Ubl chains through multivalent interactions created by nanoparticles that can be chosen based on their properties, such as abilities to augment radiation effects.
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Yi-Jia
authors.initials: YJ
authors.lastname: Li
authors.forename: Angela L
authors.initials: AL
authors.lastname: Perkins
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Ma
authors.forename: Loren
authors.initials: L
authors.lastname: Colson
authors.forename: David A
authors.initials: DA
authors.lastname: Horne
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D020816:Amino Acid Motifs; D001692:Biological Transport / Q000187:drug effects / Q000528:radiation effects; D019921:Biotinylation / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D020552:Comet Assay; D004249:DNA Damage; D006046:Gold / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D053768:Metal Nanoparticles / Q000737:chemistry*; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects / Q000528:radiation effects; D060066:Protein Interaction Maps; D011839:Radiation, Ionizing; D025841:Small Ubiquitin-Related Modifier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects
chemical_list: D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D025841:Small Ubiquitin-Related Modifier Proteins; D006046:Gold