Gene-specific DNA repair of interstrand cross-links induced by chemotherapeutic agents can be preferential.

Larminat, Florence; Zhen, Weiping; Bohr, Vilhelm A.

doi:10.1016/s0021-9258(18)53823-0

Cited by 49 publications

(5 citation statements)

References 25 publications

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“…The interstrand crosslink accounted for 5−7% of the total DNA alkylation product from CHO B11 cells treated with the structurally related bis(2-chloroethy1)methylamine (mechlorethamine, HN2) as visualized by a gel electrophoresis assays. 67 Mechlorethamine formed intrastrand cross-link in a GGC sequence in both single-(13%) and double-stranded DNA (28%) in vitro. 68 The frequency of intrastrand cross-links was ∼5.6-fold higher than interstrand cross-links in double-stranded DNA.…”

Section: ■ Resultsmentioning

confidence: 99%

“…The cross-link is a mixture of inter- and intrastrand cross-links; however, the neutral thermal hydrolysis treatment does not allow us to distinguish between interstrand and intrastrand cross-links. The interstrand cross-link accounted for 5–7% of the total DNA alkylation product from CHO B11 cells treated with the structurally related bis(2-chloroethy1)methylamine (mechlorethamine, HN2) as visualized by a gel electrophoresis assays . Mechlorethamine formed intrastrand cross-link in a GGC sequence in both single- (13%) and double-stranded DNA (28%) in vitro .…”

Section: Discussionmentioning

confidence: 99%

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Kinetics of DNA Adducts and Abasic Site Formation in Tissues of Mice Treated with a Nitrogen Mustard

Chen

Cui

Hejazi

et al. 2020

Chem. Res. Toxicol.

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Nitrogen mustards (NM) are an important class of chemotherapeutic drugs used in the treatment of malignant tumors. The accepted mechanism of action of NM is through the alkylation of DNA bases. NM-adducts block DNA replication in cancer cells by forming cytotoxic DNA interstrand cross-links. We previously characterized several adducts formed by reaction of bis(2-chloroethyl)ethylamine (NM) with calf thymus (CT) DNA and the MDA-MB-231 mammary tumor cell line. The monoalkylated N7-guanine (NM-G) adduct and its cross-link (G-NM-G) were major lesions. The cationic NM-G undergoes a secondary reaction through depurination to form an apurinic (AP) site or reacts with hydroxide to yield the stable ring-opened N 5-substituted formamidopyrimidine (NM-Fapy-G) adduct. Both of these lesions are mutagenic and may contribute to secondary tumor development, a major clinical limitation of NM chemotherapy. We established a kinetic model with NM-treated female mice and measured the rates of formation and removal of NM-DNA adducts and AP sites. We employed liquid chromatography–mass spectrometry (LC–MS) to measure NM-G, G-NM-G, and NM-Fapy-G adducts in liver, lung, and spleen over 168 h. NM-G reached a maximum level within 6 h in all organs and then rapidly declined. The G-NM-G cross-link and NM-FapyG were more persistent with half-lives over three-times longer than NM-G. We quantified AP site lesions in the liver and showed that NM treatment increased AP site levels by 3.7-fold over the basal levels at 6 h. The kinetics of AP site repair closely followed the rate of removal of NM-G; however, AP sites remained 1.3-fold above basal levels 168 h post-treatment with NM. Our data provide new insights into NM-induced DNA damage and biological processing in vivo. The quantitative measurement of the spectrum of NM adducts and AP sites can serve as biomarkers in the design and assessment of the efficacy of novel chemotherapeutic regimens.

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Section: ■ Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Kinetics of DNA Adducts and Abasic Site Formation in Tissues of Mice Treated with a Nitrogen Mustard

Chen

Cui

Hejazi

et al. 2020

Chem. Res. Toxicol.

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“…The number of ICL induced by cisplatin has been correlated with the cytotoxicity of the drug (15). Resistance of cells to cisplatin has been associated with increased gene-specific DNA repair efficiency of ICL (16)(17)(18). ICL strongly inhibit DNA transcription elongation by RNA polymerase (19).…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: Hydration at the platinated site

Coste¹,

Malinge²,

Serre³

et al. 1999

Nucleic Acids Research

193

148

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cis-diamminedichloroplatinum (II) (cisplatin) is a powerful anti-tumor drug whose target is cellular DNA. In the reaction between DNA and cisplatin, covalent intrastrand and interstrand cross-links (ICL) are formed. Two solution structures of the ICL have been published recently. In both models the double-helix is bent and unwound but with significantly different angle values. We solved the crystal structure at 100K of a double-stranded DNA decamer containing a single cisplatin ICL, using the anomalous scattering (MAD) of platinum as a unique source of phase information. We found 47 degrees for double-helix bending and 70 degrees for unwinding in agreement with previous electrophoretic assays. The crystals are stabilized by intermolecular contacts involving two cytosines extruded from the double-helix, one of which makes a triplet with a terminal G.C pair. The platinum coordination is nearly square and the platinum residue is embedded into a cage of nine water molecules linked to the cross-linked guanines, to the two amine groups, and to the phosphodiester backbone through other water molecules. This water molecule organization is discussed in relation with the chemical stability of the ICL.

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“…Finally, transcription-coupled ICL repair (TC-ICR) has been described in several experimental settings. In hamster cells, repair of ICLs is biased towards transcribed regions of the genome 15 . Loss of transcription-coupled repair proteins CSA ( ERCC8 ) or CSB ( ERCC6 ) sensitizes human cancer cells to the ICL inducing drug oxaliplatin 16 , suggesting that those proteins are required for repair of ICLs.…”

Section: Introductionmentioning

confidence: 99%

“…Transcription is another DNA transaction that influences ICL repair. Repair of ICLs is biased towards transcribed regions of the genome (8). Loss of transcription-coupled repair proteins CSA (ERCC8) or CSB (ERCC6) sensitizes cells to drugs that induce crosslinks (9), suggesting that those proteins are required for repair of ICLs.…”

Section: Introductionmentioning

confidence: 99%

Transcription-Coupled Repair of DNA Interstrand Crosslinks by UVSSA

Liebau

Waters

Ahmed

et al. 2023

Preprint

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DNA interstrand crosslinks (ICLs) are covalent bonds between opposing strands of the DNA helix which prevent DNA melting and subsequent DNA replication or RNA transcription. Here, we show that UV Stimulated Scaffold Protein A (UVSSA) participates in transcription-coupled repair of ICLs. UVSSA encodes a protein that regulates the activity of RNA polymerase II (Pol II) to facilitate the repair of UV lesions and to relieve transcription stress resulting from MYC activation. We show that UVSSA knockout sensitizes cells to ICL-inducing drugs, that UVSSA is specifically required for transcription-coupled repair of a single ICL in a fluorescence-based reporter assay, and that transcription-coupled repair of ICLs is defective in UVSSA−/−cells. UVSSA localizes to chromatin upon ICL damage, and interacts with transcribing Pol II, CSA, CSB, and TFIIH. The UVSSA-TFIIH interaction facilitates ICL repair. Finally, UVSSA expression positively correlates with ICL chemotherapy resistance in cancer cell lines. Our data strongly suggest that transcription-coupled ICL repair (TC-ICR) is abona fideICL repair mechanism that contributes to crosslinker drug resistance independently of replication-coupled ICL repair.GRAPHICAL ABSTRACTUVSSA facilitates transcription-coupled DNA interstrand crosslink repair by recruiting TFIIH to transcription machinery stalled at the lesion. Transcription-coupled ICL repair is required for survival following crosslink inducing drug exposure

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Gene-specific DNA repair of interstrand cross-links induced by chemotherapeutic agents can be preferential.

Cited by 49 publications

References 25 publications

Kinetics of DNA Adducts and Abasic Site Formation in Tissues of Mice Treated with a Nitrogen Mustard

Kinetics of DNA Adducts and Abasic Site Formation in Tissues of Mice Treated with a Nitrogen Mustard

Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: Hydration at the platinated site

Transcription-Coupled Repair of DNA Interstrand Crosslinks by UVSSA

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