Lipid-derived electrophiles mediate the effects of chemotherapeutic topoisomerase I poisons

Flor, Amy C.; Wolfgeher, Donald J.; Li, Jing; Kron, Stephen J.

doi:10.1016/j.chembiol.2020.11.011

Cited by 5 publications

(8 citation statements)

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“…Post-translational modification (PTM) of proteins increases the functional diversity in mammalian proteomes . Lipid-derived electrophile (LDE) modification is one of the most important PTM, which is associated with numerous signaling pathways and affects several biological processes due to its biological toxicity . LDEs are usually generated as the products of lipid peroxidation under oxidative stress and added to nucleophilic residues (such as cysteine, histidine, or lysine) of proteins via the nonenzymatic process.…”

Section: Introductionmentioning

confidence: 99%

“…1 Lipidderived electrophile (LDE) modification is one of the most important PTM, which is associated with numerous signaling pathways 2 and affects several biological processes due to its biological toxicity. 3 LDEs are usually generated as the products of lipid peroxidation under oxidative stress 4 and added to nucleophilic residues (such as cysteine, histidine, or lysine) of proteins via the nonenzymatic process. Most of the LDEs are derivatives of α,β-unsaturated aldehyde, which usually form LDE-protein adducts via Michael addition, including 4hydroxy-2-nonenal (HNE), 4-oxo-2-nonenal (ONE), and acrolein (ACR) as classical representatives.…”

Section: ■ Introductionmentioning

confidence: 99%

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In-Depth Profiling of 4-Hydroxy-2-nonenal Modification via Reversible Thiazolidine Chemistry

Wang,

Feng,

Liu

et al. 2024

Anal. Chem.

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Protein modification by lipid-derived electrophiles (LDEs) is associated with various signaling pathways. Among these LDEs, 4-hydroxy-2-nonenal (HNE) is the most toxic, and protein modified with HNE has been linked to various diseases, including Alzheimer’s and Parkinson’s. However, due to their low abundance, in-depth profiling of HNE modifications still presents challenges. This study introduces a novel strategy utilizing reversible thiazolidine chemistry to selectively capture HNE-modified proteins and a palladium-mediated cleavage reaction to release them. Thousands of HNE-modified sites in different cell lines were identified. Combined with ABPP, we discovered a set of HNE-sensitive sites that offer a new tool for studying LDE modifications in proteomes.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

In-Depth Profiling of 4-Hydroxy-2-nonenal Modification via Reversible Thiazolidine Chemistry

Wang,

Feng,

Liu

et al. 2024

Anal. Chem.

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“…These latter enzymes act by generating a double-stranded break in the genetic material and passing a separate double helix through the break (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013).Beyond their critical cellular functions, human topoisomerases are the targets for some of the most widely prescribed anticancer drugs worldwide (Deweese and Osheroff, 2009;Ketron and Osheroff, 2014;Pommier, 2009Pommier, , 2013. The article by Flor et al (Flor et al, 2021) in this issue of Cell Chemical Biology draws an important link between the actions of drugs that target topoisomerase I and oxidative stress in treated cells.Topoisomerase-targeted anticancer drugs rely on the fact that these enzymes generate DNA strand breaks by the nucleophilic attack of active site tyrosine residues on the sugar phosphate backbone of the double helix (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013). In order to maintain genomic integrity during DNA cleavage, topoisomerases covalently attach to the newly generated DNA termini through the formation of phosphotyrosine bonds.…”

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confidence: 99%

“…Beyond their critical cellular functions, human topoisomerases are the targets for some of the most widely prescribed anticancer drugs worldwide (Deweese and Osheroff, 2009;Ketron and Osheroff, 2014;Pommier, 2009Pommier, , 2013. The article by Flor et al (Flor et al, 2021) in this issue of Cell Chemical Biology draws an important link between the actions of drugs that target topoisomerase I and oxidative stress in treated cells.…”

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confidence: 99%

“…These derivatives, which include topotecan and the pro-drug, irinotecan, are used to treat a variety of human cancers, including lung, ovarian, and other solid tumors (Pommier, 2009(Pommier, , 2013. Although the actions of camptothecin-based drugs and other topoisomerase I poisons against the human enzyme have been well established, the article by Flor et al (Flor et al, 2021) adds another layer of complexity to the mechanism by which they induce cell death. These authors report that lipid-derived electrophiles help mediate the cellular effects of topoisomerase I poisons.…”

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confidence: 99%

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Getting stressed over topoisomerase I poisons

Osheroff

2021

Cell Chemical Biology

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Topoisomerase I is the target for a number of widely prescribed anticancer drugs that are based on camptothecin. In this issue of Cell Chemical Biology, Flor et al. demonstrate that the cellular response to camptothecin is mediated by lipid-derived electrophiles that are generated as a result of drug-induced oxidative stress.DNA topoisomerases are enzymes that regulate DNA underwinding (i.e., negative supercoiling) and overwinding (i.e., positive supercoiling) (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier et al., 2016). These enzymes relieve the torsional strain caused by the accumulation of positive DNA supercoils ahead of replication and transcription complexes and the accumulation of negative supercoils behind transcription complexes (Figure 1) by making transient breaks in the nucleic acid backbone (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013). Topoisomerase I plays an important role in alleviating this strain in human cells. The enzyme removes positive and negative supercoils by generating a single-stranded break in the double helix and allowing controlled rotation about the break (Ashley and Osheroff, 2019;Pommier, 2013). Human topoisomerase IIα and IIβ also play critical roles in alleviating torsional and axial (knotting and tangling) strain in DNA. These latter enzymes act by generating a double-stranded break in the genetic material and passing a separate double helix through the break (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013).Beyond their critical cellular functions, human topoisomerases are the targets for some of the most widely prescribed anticancer drugs worldwide (Deweese and Osheroff, 2009;Ketron and Osheroff, 2014;Pommier, 2009Pommier, , 2013. The article by Flor et al. (Flor et al., 2021) in this issue of Cell Chemical Biology draws an important link between the actions of drugs that target topoisomerase I and oxidative stress in treated cells.Topoisomerase-targeted anticancer drugs rely on the fact that these enzymes generate DNA strand breaks by the nucleophilic attack of active site tyrosine residues on the sugar phosphate backbone of the double helix (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013). In order to maintain genomic integrity during DNA cleavage, topoisomerases covalently attach to the newly generated DNA termini through the formation of phosphotyrosine bonds. These hallmark covalent enzyme-cleaved DNA complexes are DECLARATION OF INTERESTSThe author declares no competing interests.

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Isolation and detection of DNA–protein crosslinks in mammalian cells

Torrecilla,

Ruggiano,

Kiianitsa

et al. 2023

Nucleic Acids Research

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DNA–protein crosslinks (DPCs) are toxic DNA lesions wherein a protein is covalently attached to DNA. If not rapidly repaired, DPCs create obstacles that disturb DNA replication, transcription and DNA damage repair, ultimately leading to genome instability. The persistence of DPCs is associated with premature ageing, cancer and neurodegeneration. In mammalian cells, the repair of DPCs mainly relies on the proteolytic activities of SPRTN and the 26S proteasome, complemented by other enzymes including TDP1/2 and the MRN complex, and many of the activities involved are essential, restricting genetic approaches. For many years, the study of DPC repair in mammalian cells was hindered by the lack of standardised assays, most notably assays that reliably quantified the proteins or proteolytic fragments covalently bound to DNA. Recent interest in the field has spurred the development of several biochemical methods for DPC analysis. Here, we critically analyse the latest techniques for DPC isolation and the benefits and drawbacks of each. We aim to assist researchers in selecting the most suitable isolation method for their experimental requirements and questions, and to facilitate the comparison of results across different laboratories using different approaches.

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Lipid-derived electrophiles mediate the effects of chemotherapeutic topoisomerase I poisons

Cited by 5 publications

References 79 publications

In-Depth Profiling of 4-Hydroxy-2-nonenal Modification via Reversible Thiazolidine Chemistry

In-Depth Profiling of 4-Hydroxy-2-nonenal Modification via Reversible Thiazolidine Chemistry

Getting stressed over topoisomerase I poisons

Isolation and detection of DNA–protein crosslinks in mammalian cells

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