Publications by authors named "Cameron Rzadki"

2 Publications

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Identification of Bioactive SNM1A Inhibitors.

ACS Omega 2021 Apr 31;6(14):9352-9361. Epub 2021 Mar 31.

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4L8, Canada.

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.
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http://dx.doi.org/10.1021/acsomega.0c03528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047731PMC
April 2021

Structure-specific endonuclease activity of SNM1A enables processing of a DNA interstrand crosslink.

Nucleic Acids Res 2018 09;46(17):9057-9066

Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster, University, Hamilton, Ontario L8N 3Z5, Canada.

DNA interstrand crosslinks (ICLs) covalently join opposing strands, blocking both replication and transcription, therefore making ICL-inducing compounds highly toxic and ideal anti-cancer agents. While incisions surrounding the ICL are required to remove damaged DNA, it is currently unclear which endonucleases are needed for this key event. SNM1A has been shown to play an important function in human ICL repair, however its suggested role has been limited to exonuclease activity and not strand incision. Here we show that SNM1A has endonuclease activity, having the ability to cleave DNA structures that arise during the initiation of ICL repair. In particular, this endonuclease activity cleaves single-stranded DNA. Given that unpaired DNA regions occur 5' to an ICL, these findings suggest SNM1A may act as either an endonuclease and/or exonuclease during ICL repair. This finding is significant as it expands the potential role of SNM1A in ICL repair.
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http://dx.doi.org/10.1093/nar/gky759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158701PMC
September 2018