publications

2024

1. 

   The Fanconi anemia pathway repairs colibactin-induced DNA interstrand cross-links

   Maria Altshuller, Xu He, Elliot J. MacKrell, and 9 more authors

   bioRxiv, 2024

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   Colibactin is a secondary metabolite produced by bacteria present in the human gut and is implicated in the progression of colorectal cancer and inflammatory bowel disease. This genotoxin alkylates deoxyadenosines on opposite strands of host cell DNA to produce DNA interstrand cross-links (ICLs) that block DNA replication. While cells have evolved multiple mechanisms to resolve (“unhook”) ICLs encountered by the replication machinery, little is known about which of these pathways promote resistance to colibactin-induced ICLs. Here, we use Xenopus egg extracts to investigate replication-coupled repair of plasmids engineered to contain site-specific colibactin-ICLs. We show that replication fork stalling at a colibactin-ICL leads to replisome disassembly and activation of the Fanconi anemia ICL repair pathway, which unhooks the colibactin-ICL through nucleolytic incisions. These incisions generate a DNA double-strand break intermediate in one sister chromatid, which can be repaired by homologous recombination, and a monoadduct (“ICL remnant”) in the other. Our data indicate that translesion synthesis past the colibactin-ICL remnant depends on Polη and a Polκ-REV1-Polζ polymerase complex. Although translesion synthesis past colibactin-induced DNA damage is frequently error-free, it can introduce T>N point mutations that partially recapitulate the mutation signature associated with colibactin exposure in vivo. Taken together, our work provides a biochemical framework for understanding how cells tolerate a naturally-occurring and clinically-relevant ICL.Competing Interest StatementThe authors have declared no competing interest.

2023

1. 

   Tidyproteomics: an open-source R package and data object for quantitative proteomics post analysis and visualization

   Jeff Jones, Elliot J. MacKrell, Ting-Yu Wang, and 3 more authors

   BMC Bioinformatics, Jun 2023

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   The analysis of mass spectrometry-based quantitative proteomics data can be challenging given the variety of established analysis platforms, the differences in reporting formats, and a general lack of approachable standardized post-processing analyses such as sample group statistics, quantitative variation and even data filtering. We developed tidyproteomics to facilitate basic analysis, improve data interoperability and potentially ease the integration of new processing algorithms, mainly through the use of a simplified data-object.

2015

1. 

   Biodegradable and pH-Responsive Nanoparticles Designed for Site-Specific Delivery in Agriculture

   Megan R. Hill, Elliot J. MacKrell, Carl P. Forsthoefel, and 5 more authors

   Biomacromolecules, Jun 2015

   PMID: 25756603

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   We report the synthesis and characterization of pH-responsive polysuccinimide-based nanoparticles. Polysuccinimide (PSI), a precursor to biodegradable poly(aspartic acid), was synthesized from the condensation of l-aspartic acid and subsequently functionalized with primary amines to form random amphiphilic copolymers. The copolymers formed stable nanoparticles in aqueous medium via nanoprecipitation and were subsequently loaded with a model hydrophobic molecule to demonstrate their potential as controlled-release delivery vehicles. It was found that above pH 7, the hydrophobic succinimidyl units of the PSI nanoparticles hydrolyzed to release encapsulated materials. The release rate significantly increased at elevated pH and decreased with an increasing degree of functionalization. Finally, plant toxicity studies showed that the polymer materials exhibit little to no toxic effects at biologically relevant concentrations.