DNA-dependent protease activity of human Spartan facilitates replication of DNA–protein crosslink-containing DNA

Mórocz, Mónika; Zsigmond, Eszter; Toth, Robert; Enyedi, Márton Zsolt; Pintér, Lajos; Haracska, Lajos

doi:10.1093/nar/gkw1315

Cited by 65 publications

(119 citation statements)

References 61 publications

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“…48 Recently, the metalloprotease SPRTN has been identified by several laboratories as the mammalian protease responsible for cleaving DPCs at blocked replication forks. 49–51 …”

Section: Discussionmentioning

confidence: 99%

Mass Spectrometry Based Proteomics Study of Cisplatin-Induced DNA–Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells

Ming

Groehler

Michaelson-Richie

et al. 2017

Chem. Res. Toxicol.

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Platinum-based antitumor drugs such as 1,1,2,2-cis-diamminedichloroplatinum(II) (cisplatin), carboplatin, and oxaliplatin are currently used to treat nearly 50% of all cancer cases, and novel platinum based agents are under development. The antitumor effects of cisplatin and other platinum compounds are attributed to their ability to induce interstrand DNA-DNA cross-links, which are thought to inhibit tumor cell growth by blocking DNA replication and/or preventing transcription. However, platinum agents also induce significant numbers of unusually bulky and helix-distorting DNA-protein cross-links (DPCs), which are poorly characterized because of their unusual complexity. We and others have previously shown that model DPCs block DNA replication and transcription and cause toxicity in human cells, potentially contributing to the biological effects of platinum agents. In the present work, we have undertaken a system-wide investigation of cisplatin-mediated DNA-protein cross-linking in human fibrosarcoma (HT1080) cells using mass spectrometry-based proteomics. DPCs were isolated from cisplatin-treated cells using a modified phenol/chloroform DNA extraction in the presence of protease inhibitors. Proteins were released from DNA strands and identified by mass spectrometry-based proteomics and immunological detection. Over 250 nuclear proteins captured on chromosomal DNA following treatment with cisplatin were identified, including high mobility group (HMG) proteins, histone proteins, and elongation factors. To reveal the exact molecular structures of cisplatin-mediated DPCs, isotope dilution HPLC-ESI+-MS/MS was employed to detect 1,1-cis-diammine-2-(5-amino-5-carboxypentyl)amino-2-(2′-deoxyguanosine-7-yl)-platinum (II) (dG-Pt-Lys) conjugates between the N7 guanine of DNA and the ε-amino group of lysine. Our results demonstrate that therapeutic levels of cisplatin induce a wide range of DPC lesions, which likely contribute to both target and off target effects of this clinically important drug.

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“…48 Recently, the metalloprotease SPRTN has been identified by several laboratories as the mammalian protease responsible for cleaving DPCs at blocked replication forks. 49–51 …”

Section: Discussionmentioning

confidence: 99%

Mass Spectrometry Based Proteomics Study of Cisplatin-Induced DNA–Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells

Ming

Groehler

Michaelson-Richie

et al. 2017

Chem. Res. Toxicol.

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“…The mammalian dvc-1 ortholog, Spartan, is a constitutive component of the replication machinery and is required for replication-coupled DPC repair (Lopez-Mosqueda et al, 2016;Maskey et al, 2017;Morocz et al, 2017;Vaz et al, 2016). Spartan is expressed primarily during the S and G2 phase of the cell cycle; it is regulated by APC-Cdh1 and degraded in mitosis (Mosbech et al, 2012).…”

Section: Gcna-1 Is Cell Cycle Regulated and Localizes To Condensed Chmentioning

confidence: 99%

GCNA interacts with Spartan and Topoisomerase II to regulate genome stability

Davis

Dokshin

Sawle

et al. 2019

Preprint

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“…DNA damage hinders replication, and may lead to strand breaks, genomic instability, aging and cancer [65]. DNA-topoisomerase 1 crosslinks (DPC) are bulky lesions that trap otherwise transient covalent DNA-protein intermediates, and inhibit movement of polymerases and helicase, causing stalling of the replication fork.…”

Section: Regulation Of Physiological Processesmentioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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DNA-dependent protease activity of human Spartan facilitates replication of DNA–protein crosslink-containing DNA

Cited by 65 publications

References 61 publications

Mass Spectrometry Based Proteomics Study of Cisplatin-Induced DNA–Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells

Mass Spectrometry Based Proteomics Study of Cisplatin-Induced DNA–Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells

GCNA interacts with Spartan and Topoisomerase II to regulate genome stability

Proteases: Pivot Points in Functional Proteomics

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