Characterization of bifunctional adducts produced in DNA by trans-diamminedichloroplatinum(II)

Eastman, Alan; Jennerwein, Margaretha; Nagel, Donald

doi:10.1016/0009-2797(88)90087-7

Cited by 77 publications

(80 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The platination procedure yielded 1.5 F 1.4 pg/Ag DNA, which is equivalent to 9.3 adducts per plasmid or 3.2 adducts per Luc-coding region and promoter as previously reported (38). Similar levels of platination have previously been shown not to affect the efficiency of transfection (39). One microgram of randomly platinated or unplatinated pRL-CMV vector was transfected for 6 hours into the cells as described above.…”

Section: Methodssupporting

confidence: 61%

DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair

Lin

Trang

Okuda

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

The mutagenicity of cis-diamminedichloroplatinum(II) (DDP; cisplatin) and the rate at which resistance develops with repeated exposure to DDP are dependent on mutagenic translesional replication across DDP DNA adducts, mediated in part by DNA polymerase~, and on the integrity of the DNA mismatch repair (MMR) system. The aim of this study was to determine whether disabling Pol~by suppressing expression of its hREV3 subunit in human cancer cells can reduce the mutagenicity of DDP and whether loss of MMR facilitates mutagenic Pol~-dependent translesional bypass. The HCT116+ch3 (MMR + /REV3 + ) and HCT116 (MMR À /REV3 + ) human colon carcinoma cell lines were engineered to suppress hREV3 mRNA by stable expression of a short hairpin interfering RNA targeted to hREV3. The effect of knocking down REV3 expression was to completely offset the DDP resistance mediated by loss of MMR. Knockdown of REV3 also reduced the mutagenicity of DDP and eliminated the enhanced mutagenicity of DDP observed in the MMR À /REV3 + cells. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. We conclude that Pol~plays a central role in the mutagenic bypass of DDP adducts and that the DDP resistance, enhanced mutagenicity, and the increased capacity of MMR À /REV3 + cells to express a gene burdened by DDP adducts are all dependent on the Pol~pathway.

show abstract

Section: Methodssupporting

confidence: 61%

DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair

Lin

Trang

Okuda

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…), which is equivalent to 9.3 adducts per plasmid or 3.2 adducts per Luc coding region and promoter as we reported previously (Cenni et al, 1999). Similar levels of platination have been shown previously not to affect the efficiency of transfection (Eastman et al, 1988). One microgram of randomly platinated or unplatinated pRL-CMV vector was transfected for 6 h into the cells, as described above.…”

Section: Methodsmentioning

confidence: 66%

Human REV1 Modulates the Cytotoxicity and Mutagenicity of Cisplatin in Human Ovarian Carcinoma Cells

Lin

Okuda²,

Trang³

et al. 2006

Mol Pharmacol

View full text Add to dashboard Cite

REV1 interacts with Y-type DNA polymerases (Pol) and Pol to bypass many types of adducts that block the replicative DNA polymerases. This pathway accounts for many of the mutations induced by cisplatin (cis-diamminedichloroplatinium II, DDP). This study sought to determine how increasing human REV1 (hREV1) affects the cytotoxicity and mutagenicity of DDP. Human ovarian carcinoma 2008 cells were transfected with an hREV1 expression vector and 4 sublines developed in which the hREV1 mRNA level was increased by 6.3-to 23.4-fold and hREV1 protein by 2.7-to 6.2-fold. The sublines were 1.3-to 1.7-fold resistant to the cytotoxic effect of DDP and 2.3-to 5.1-fold hypersensitive to the mutagenic effect of DDP. The hREV1-transfected sublines were 1.5-to 1.8-fold better than the parental 2008 cells at managing DDP adducts as assessed by their ability to express Renilla reniformis luciferase from a vector that had been extensively loaded with DDP adducts before transfection. Increased hREV1 expression was associated with a 1.5-fold increase in the rate at which the whole population acquired resistance to DDP during sequential cycles of drug exposure. Increasing the abundance of hREV1 thus resulted in both resistance to DDP and a significant elevation in DDP-induced mutagenicity. This was accompanied by an enhanced capacity to synthesize a functional protein from a DDPdamaged gene and, most importantly, by more rapid development of resistance during sequential cycles of DDP exposure that mimic clinical schedules of DDP administration. We conclude that hREV1-dependent processes are important determinants of DDP-induced genomic instability and the development of resistance.

show abstract

“…Some of the monoadducts slowly rearrange to diadducts, with 50% of trans-DDP adducts remaining as monoadducts after a 24 hour incubation (9). The diadducts formed by trans-DDP include DNA interstrand cross-links (2% of trans-DDP adducts in isolated Nucleic Acids Research mammalian DNA) (11), and probably 1,3 intrastrand cross-links or cross-links between further separated base residues (12).…”

Section: Introductionmentioning

confidence: 99%

Repair synthesis by human cell extracts in DNA damaged bycis- andtrans-diamminedichloroplatinum(II)

Hansson¹,

Wood

1989

Nucl Acids Res

109

View full text Add to dashboard Cite

DNA damage was induced in closed circular plasmid DNA by treatment with cis-or transdiamminedichloroplatinum(l). These plasmids were used as substrates in reactions to give quantitative measurements of DNA repair synthesis mediated by cell free extracts from human lymphoid cell lines. Adducts induced by both drugs stimulated repair synthesis in a dose dependent manner by an ATP-requiring process. Measurements by an isopycnic gradient sedimentation method gave an upper limit for the average patch sizes in this in vitro system of around 140 nucleotides. It was estimated that up to 3% of the drug adducts induce the synthesis of a repair patch. The repair synthesis is due to repair of a small fraction of frequent drug adducts, rather than extensive repair of a rare subclass of lesions. Nonspecific DNA synthesis in undamaged plasmids, caused by exonucleolytic degradation and resynthesis, was reduced by repeated purification of intact circular forms. An extract made from cells belonging to xeroderma pigmentosum complementation group A was deficient in repair synthesis in response to the presence of cis-or trans-diamminedichloroplatinum(ll) adducts in DNA.

show abstract

Characterization of bifunctional adducts produced in DNA by trans-diamminedichloroplatinum(II)

Cited by 77 publications

References 11 publications

DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair

DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair

Human REV1 Modulates the Cytotoxicity and Mutagenicity of Cisplatin in Human Ovarian Carcinoma Cells

Repair synthesis by human cell extracts in DNA damaged bycis- andtrans-diamminedichloroplatinum(II)

Contact Info

Product

Resources

About