Structures of Silver Fingers and a Pathway to Their Genotoxicity

• Published in: Angewandte Chemie International Edition Vol. 61; no. 12; pp. e202116621 - n/a
• Main Authors: Kluska, Katarzyna, Veronesi, Giulia, Deniaud, Aurélien, Hajdu, Bálint, Gyurcsik, Béla, Bal, Wojciech, Krężel, Artur
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 14-03-2022; Wiley-VCH Verlag; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Absorption spectroscopy; Biochemistry, Molecular Biology; Chemical Sciences; Clusters; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA Binding; DNA-Binding Proteins - chemistry; Genotoxicity; Life Sciences; Material chemistry; Proteins; Silver; Silver - chemistry; Silver Clusters; Sulfur; Transcription Factors - chemistry; X-ray Absorption Spectroscopy; Zinc finger proteins; Zinc Fingers; Zinc Fingers; X-ray Absorption Spectroscopy; Silver Clusters; DNA Binding
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202116621

Recently, we demonstrated that AgI can directly replace ZnII in zinc fingers (ZFs). The cooperative binding of AgI to ZFs leads to a thermodynamically irreversible formation of silver clusters destroying the native ZF structure. Thus, a reported loss of biological function of ZF proteins is a likely consequence of such replacement. Here, we report an X‐ray absorption spectroscopy (XAS) study of AgnSn clusters formed in ZFs to probe their structural features. Selective probing of the local environment around AgI by XAS showed the predominance of digonal AgI coordination to two sulfur donors, coordinated with an average Ag−S distance at 2.41 Å. No Ag−N bonds were present. A mixed AgS2/AgS3 geometry was found solely in the CCCH AgI−ZF. We also show that cooperative replacement of ZnII ions with the studied Ag2S2 clusters occurred in a three‐ZF transcription factor protein 1MEY#, leading to a dissociation of 1MEY# from the complex with its cognate DNA.
The cooperative AgI binding to CCHH zinc fingers causes zinc ion release followed by a collapse of the stable secondary structure and formation of a highly stable Ag2S2 cluster. CCHC, CCCH and CCCC zinc fingers react analogously. Such silver‐induced perturbation inhibits binding of the CCHH zinc finger protein to its cognate DNA sequence and as a consequence may affect many cellular processes including transcriptional regulation.