Base‐Resolution Analysis of Cisplatin–DNA Adducts at the Genome Scale

Shu, Xiaoting; Xiong, Xushen; Song, Jinghui; He, Chuan; Yi, Chengqi

doi:10.1002/anie.201607380

Cited by 79 publications

(68 citation statements)

References 32 publications

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“…In general, GC‐rich DNA in the highest multicellular organisms constitutes gene‐rich actively‐transcribed genomic regions. It was recently established that cis ‐platin, another DNA alkylating agent, targets promoters and regions harboring transcription termination sites in genomic DNA . Our results suggest that, upon treatment with DMC, regions of mammalian DNA with a high CG content are likely to be rich in 1”‐α dG adducts whereas regions with a low CG content are likely to be rich in 1“‐β dG adducts.…”

Section: Discussionmentioning

confidence: 63%

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Aguilar

Paz

Vargas

et al. 2018

Chemistry A European J

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Mitomycin C (MC), an antitumor drug, and decarbamoylmitomycin C (DMC), a derivative of MC, alkylate DNA and form deoxyguanosine monoadducts and interstrand crosslinks (ICLs). Interestingly, in mammalian culture cells, MC forms primarily deoxyguanosine adducts with a 1"-R stereochemistry at the guanine-mitosene bond (1"-α) whereas DMC forms mainly adducts with a 1"-S stereochemistry (1"-β). The molecular basis for the stereochemical configuration exhibited by DMC has been investigated using biomimetic synthesis. Here, we present the results of our studies on the monoalkylation of DNA by DMC. We show that the formation of 1"-β-deoxyguanosine adducts requires bifunctional reductive activation of DMC, and that monofunctional activation only produces 1"-α-adducts. The stereochemistry of the deoxyguanosine adducts formed is also dependent on the regioselectivity of DNA alkylation and on the overall DNA CG content. Additionally, we found that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by mitomycins: At 0 °C, both deoxyadenosine (dA) and deoxyguanosine (dG) alkylation occur whereas at 37 °C, mitomycins alkylate dG preferentially. The new reaction protocols developed in our laboratory to investigate DMC-DNA alkylation raise the possibility that oligonucleotides containing DMC 1"-β-deoxyguanosine adducts at a specific site may be synthesized by a biomimetic approach.

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Section: Discussionmentioning

confidence: 63%

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Aguilar

Paz

Vargas

et al. 2018

Chemistry A European J

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“…The discovery of cisplatin by Rosenberg led to incredible advances in medicinal chemistry, particularly in cancer treatment . Therefore, many organometallic or coordination platinum complexes have been prepared and tested as possible candidates for anticancer drug development .…”

Section: Introductionmentioning

confidence: 99%

Cyclometalated Platinum(II) Complexes Comprising 2‐(Diphenylphosphino)pyridine and Various Thiolate Ligands: Synthesis, Spectroscopic Characterization, and Biological Activity

et al. 2017

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The known cyclometalated platinum(II) complex [Pt(ppy)(DMSO)(Cl)] (A) in which ppy = 2‐phenylpyridinate, was treated with 2‐(diphenylphosphino)pyridine (PPh2py, PN) (1 equiv.) and readily afforded complex [Pt(ppy)(PPh2py‐κ1P)(Cl)] (1). The transphobia effect (T) and single‐crystal X‐ray diffraction crystallography confirmed that the phosphine ligand in 1 is located trans to the nitrogen atom of the cyclometalating fragment (ppy). Compound 1 was treated with various thiolate reagents (1 equiv.) at room temperature, leading to the displacement of the chloride ligand in 1 by thiolate ligands through a salt metathesis reaction. The reaction led to the formation of a series of monomeric complexes with the general formula [Pt(ppy)(PPh2py‐κ1P)(SR)] (2a–2d), where SR = deprotonated form of pyridine‐2‐thiol (HSpy, 2a), pyrimidine‐2‐thiol (HSpyN, 2b), thiophenol (HSPh, 2c), and 2‐thiazoline‐2‐thiol (HSt, 2d). All complexes have been characterized by NMR spectroscopy. The biological activities of the complexes were evaluated against three human cancer cell lines, including A549 (human lung cancer), SKOV3 (human ovarian cancer), and MCF7 (human breast cancer), by means of the MTT assay [MTT = 3‐(4,5‐dimethylthiazol‐yl)‐2,5‐diphenyltetrazolium bromide]. Compounds 2a and 2b presented effective, potent cytotoxic activity regarding the cell lines. Electrophoretic mobility shift assays on plasmid DNA and molecular modeling investigations were also performed to determine the specific binding mode or the binding orientation of the complexes to DNA.

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“…Following aquation, or replacement of the chloride ligands in [Pt(NH 3 ) 2 Cl 2 ] by water, the activated drug binds to DNA, generating mainly 1,2-intrastrand d(GpG) cross-links that block RNA polymerase II, ultimately signaling cell death (9)(10)(11). Recently, a cisplatinsequencing (cisplatin-seq) approach was used to confirm DNA as the target for cisplatin at the genome scale by base resolution analysis (12). High-mobility group proteins such as high-mobility group box protein 1 (HMGB1) recognize these specific cisplatin-DNA adducts and promote the toxicity of cisplatin to tumors by interfering with excision and other repair pathways (13,14).…”

mentioning

confidence: 99%

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

Awuah

Riddell

Lippard

2017

Proc. Natl. Acad. Sci. U.S.A.

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Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, uniquely blocks excision repair of cisplatin-DNA adducts, 1,2-intrastrand cross-links, to potentiate the sensitivity of TGCTs to cisplatin therapy. We used CRISPR/ Cas9-mediated gene editing to knockout the HMGB4 gene in a testicular human embryonic carcinoma and examined cellular responses. We find that loss of HMGB4 elicits resistance to cisplatin as evidenced by cell proliferation and apoptosis assays. We demonstrate that HMGB4 specifically inhibits repair of the major cisplatin-DNA adducts in TGCT cells by using the human TGCT excision repair system. Our findings also reveal characteristic HMGB4-dependent differences in cell cycle progression following cisplatin treatment. Collectively, these data provide convincing evidence that HMGB4 plays a major role in sensitizing TGCTs to cisplatin, consistent with shielding of platinum-DNA adducts from excision repair.platinum anticancer drug | testicular cancer | high-mobility group protein T esticular germ cell tumors (TGCTs) are among the few tumor types that can be clinically cured with chemotherapy owing to the potency of cisplatin (1). The introduction of cisplatin in combination chemotherapy helped advance cure rates from 5% to the current level of 90% (2). In the clinic, cisplatin is used with bleomycin and either vinblastine or etoposide to treat metastatic testicular neoplasms (3-6). The well-studied antitumor activity of cisplatin involves binding to DNA, inhibition of transcription, and induction of apoptosis (7,8). Cellular events leading to apoptosis are multifactorial and begin with uptake followed by chemical transformation of cisplatin. Following aquation, or replacement of the chloride ligands in [Pt(NH 3 ) 2 Cl 2 ] by water, the activated drug binds to DNA, generating mainly 1,2-intrastrand d(GpG) cross-links that block RNA polymerase II, ultimately signaling cell death (9-11). Recently, a cisplatinsequencing (cisplatin-seq) approach was used to confirm DNA as the target for cisplatin at the genome scale by base resolution analysis (12). High-mobility group proteins such as high-mobility group box protein 1 (HMGB1) recognize these specific cisplatin-DNA adducts and promote the toxicity of cisplatin to tumors by interfering with excision and other repair pathways (13,14).HMGB1 binds selectively to cisplatin 1,2-intrastrand d(GpG) and d(ApG) cross-links, which account for ∼90% of all platinum (Pt)-DNA adducts (15,16). Studies of the interaction of HMGB1 and other cisplatin-DNA recognition proteins such as Irx1 in yeast (17, 18) with cisplatin-modified DNA revealed bending of the DNA with attendant shielding from excision repair in vitro and subsequent sensitization of cancer cells to cisplatin treatment (13,19). Related studies showed cooperative HMGB1 and XP...

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Base‐Resolution Analysis of Cisplatin–DNA Adducts at the Genome Scale

Cited by 79 publications

References 32 publications

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Cyclometalated Platinum(II) Complexes Comprising 2‐(Diphenylphosphino)pyridine and Various Thiolate Ligands: Synthesis, Spectroscopic Characterization, and Biological Activity

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

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