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-SUMOchain-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.polyubiquitin chain | radiation sensitization | SUMO-binding motif (SBM) | SUMO-interacting motif (SIM) P rotein-protein interactions mediated by mono-Ubl (ubiquitinlike proteins) or poly-Ubl modifications are among the most important signaling and regulatory mechanisms that control nearly every aspect of cellular functions (1). It has been well established that the small ubiquitin-like modifiers (SUMO), SUMO-1, SUMO-2, and SUMO-3, play essential roles in cellular response to DNA damage (2). SUMO-2 and -3 are nearly identical, but share less than 50% sequence homology to SUMO-1 (3, 4). SUMO-2 and 3 are distinct from SUMO-1 in that they carry internal SUMO modification sites at their N-termini to form poly-SUMO chains (5).In most cases, a Ubl serves as a platform for interactions with other proteins. For instance, ubiquitylation dependent processes are mediated by ubiquitin-binding motifs in receptor proteins, such as the proteosome (6). SUMO-dependent functions are mediated by a SUMO-interaction motif (SIM; also known as a SUMO-binding motif, SBM) (7, 8) that serves as receptor of SUMO modified proteins. Recent studies have shown that a SUMO-targeted ubiquitin ligase (STUBL) is important in DNA damage response, and the ligase specifically recognizes poly-SUMO-2∕3 chains to ubiquitinate poly-SUMO modified proteins for degradation (9)(10)(11)(12)(13)(14). These studies suggest that inhibiting poly-SUMO-2∕3 interactions with down-stream effectors, such as STUBL, can inhibit DNA damage response. However, an effective approach to disrupting poly-Ubl chain-mediated cellular functions is lacking. In addition to proteosome inhibitors, a small molecule was identified that binds to and alters the conformation of polyubiquitin chains such that their interactions with the proteosome are inhibited (15). However, the negative charge of this small molecule prevents its translocation into cells.Both ionizing radiation and most chemotherap...

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search

“…S1A). Consistently, we note that besides Val and Ile, Thr is also frequently associated with known SIMs, most likely because as ␤-branched amino acids, Thr, Val, and Ile all have the greatest propensity to form a ␤-strand (36,37). Therefore, for future improvements, secondary structure prediction algorithms may be combined with the string search to achieve a more accurate SIM prediction.…”

“…Likewise, chemical mimetics of VIDLT may disrupt overall SUMO-SIM interaction and impair the activity of sumoylation essential for living cells, e.g. during their recovery from genotoxic stress (37). We further speculate that the dominant SIMs drive a "zipping-up" process during the recognition between clustered SIMs and multiple SUMO moieties, which likely initiates in a dynamic manner before adopting a stable configuration.…”

Metabolizable Bi2Se3 Nanoplates: Biodistribution, Toxicity, and Uses for Cancer Radiation Therapy and Imaging

“…Bi is a high atomic number material (Z = 83) and it has a high photoelectric absorption coefficient (5.3 cm 2 /g at 100 keV), which is higher than those of I, Au, and Pt. The large X‐ray absorption is advantageous for use as a cancer radio sensitizer and X‐ray contrast agent . Thus, Bi 2 Se 3 nanoparticles deserve a thorough biomedical investigation regarding their high radiation enhancement effect and possible use in cancer radiation therapy.…”

Inhibitors targeting the SUMOylation pathway: A patent review 2012‑2015 (Review)

“…Therefore, the conjugation of a weak SUMO-2/3 ligand to AuNPs promotes selective multivalent interactions with poly-SUMO-2/3 chains, resulting in the efficient inhibition of poly-SUMO-chain-mediated protein-protein interactions (5). Metals with high atomic numbers, such as gold, preferentially absorb more X-ray energy than soft tissues, thus augmenting the effects of ionizing radiation when delivered to cells (28,29). Application.…”