SNM1A is a nuclease required to repair DNA interstrand cross-links (ICLs) caused by some anticancer compounds, including cisplatin. Unlike other nucleases involved in ICL repair, SNM1A is not needed to restore other forms of DNA damage. As such, SNM1A is an attractive target for selectively increasing the efficacy of ICL-based chemotherapy. Using a fluorescence-based exonuclease assay, we screened a bioactive library of compounds for inhibition of SNM1A. Of the 52 compounds initially identified as hits, 22 compounds showed dose-response inhibition of SNM1A. An orthogonal gel-based assay further confirmed nine small molecules as SNM1A nuclease activity inhibitors with IC values in the mid-nanomolar to low micromolar range. Finally, three compounds showed no toxicity at concentrations able to significantly potentiate the cytotoxicity of cisplatin. These compounds represent potential leads for further optimization to sensitize cells toward chemotherapeutic agents inducing ICL damage.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047731 | PMC |
| http://dx.doi.org/10.1021/acsomega.0c03528 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Article Synopsis
- - The SNM1A exonuclease is crucial for repairing interstrand crosslinks (ICLs) in DNA, and it interacts with the Cockayne Syndrome B protein (CSB) during transcription-coupled DNA repair.
- - The research shows that certain regions in CSB, particularly the C-terminal region, are essential for binding and enhancing the activity of SNM1A, especially in its ability to process ICLs.
- - The findings suggest that targeting the specific protein interactions that boost SNM1A's function may offer a new therapeutic strategy for treating conditions related to DNA damage, rather than just inhibiting the nuclease's active site.
Zinc-Binding Oligonucleotide Backbone Modifications for Targeting a DNA-Processing Metalloenzyme.
Chembiochem
November 2024
School of Chemistry and Trinity Biomedical Sciences Institute, Trinity College Dublin, the University of Dublin, Dublin 2, Ireland.
A series of chemically-modified oligonucleotides for targeting the DNA repair nuclease SNM1A have been designed and synthesised. Each oligonucleotide contains a modified internucleotide linkage designed to both mimic the native phosphodiester backbone and chelate to the catalytic zinc ion(s) in the SNM1A active site. Dinucleoside phosphoramidites containing urea, squaramide, sulfanylacetamide, and sulfinylacetamide linkages were prepared and employed successfully in solid-phase oligonucleotide synthesis.
View Article and Find Full Text PDFCell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.
Chem Sci
May 2024
Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford Mansfield Road Oxford OX1 3TA UK
The three human SNM1 metallo-β-lactamase fold nucleases (SNM1A-C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site.
View Article and Find Full Text PDFDeploying solid-phase synthesis to access thymine-containing nucleoside analogs that inhibit DNA repair nuclease SNM1A.
Org Biomol Chem
July 2023
Department of Biology and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Nucleoside analogs show useful bioactive properties. A versatile solid-phase synthesis that readily enables the diversification of thymine-containing nucleoside analogs is presented. The utility of the approach is demonstrated with the preparation of a library of compounds for analysis with SNM1A, a DNA damage repair enzyme that contributes to cytotoxicity.
View Article and Find Full Text PDFBreak-induced replication orchestrates resection-dependent template switching.
Nature
July 2023
Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Article Synopsis
- Break-induced telomere synthesis (BITS) is a RAD51-independent process essential for alternative telomere lengthening, using a simple replication mechanism with PCNA and DNA polymerase-δ for DNA repair.
- The study combines double-strand break induction with proteomics to explore the telomeric DNA damage response during BITS, revealing a significant role for repair synthesis and RAD18-dependent PCNA ubiquitination in managing replication stress.
- SNM1A nuclease emerges as a key player, recognizing ubiquitinated PCNA at damaged telomeres and facilitating resection, highlighting its importance in DNA repair and lesion bypass in mammalian cells.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!