Mitomycins and Porfiromycin: Chemical Mechanism of Activation and Cross-linking of DNA

Iyer, V. N.; Szybalski, Waclaw

doi:10.1126/science.145.3627.55

Cited by 557 publications

(275 citation statements)

References 11 publications

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“…When interpreting these results, it is important to consider that although it is unlikely that MMC will trigger lesions within the EGFP coding region, the survival assay is monitoring the effect of MMC-induced interstrand cross-links (ICLs) in the whole genome. Given that ICLs, although representing only one MMC-DNA adduct out of many, are the major source of cytotoxicity (28)(29)(30)(31), it is tempting to speculate that the survival assay is revealing the contribution of p53 to the resolution of ICLs. It is interesting that this scenario is different from the one observed after introduction of DSBs by ionizing radiation (IR).…”

Section: Resultsmentioning

confidence: 99%

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

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

161

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DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonucleasedeficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linkerinduced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.T he tumor suppressor protein p53 has been called the guardianof-the-genome due to its ability to transactivate downstream targets transcriptionally, which prevents S-phase entrance before facilitating DNA repair or eliminating cells with severe DNA damage via apoptosis (1). Interestingly, p53 also encodes an intrinsic 3′-5′ exonuclease activity located within its central DNA-binding domain (2-4). The contribution of the exonuclease proficiency to p53's function has largely remained obscure. Exonucleases are involved in DNA replication, DNA repair, and recombination, increasing the fidelity or efficiency of these processes. The 3′-5′ exonuclease activity of DNA polymerases (POLs) catalyzes the correction of replication errors, thereby preventing genomic instability and cancer (5-7). The potential involvement of p53's exonuclease in DNA repair has been ascribed to transcription-independent functions in nucleotide excision repair and base excision repair, in homologous recombination (HR), and in mitochondrial processes (8-10).Regarding HR, in particular, reports indicate a dual role for p53. On the one hand, it has been reported that p53 down-regulates unscheduled and excessive HR in response to severe genotoxic stress, like formation of DNA double-strand breaks (DSBs) (8-10). This antirecombinogenic effect of p53 has been linked to the blockage of continued strand exchange by interactions with recombinase RAD51, RAD54, and nascent HR intermediates carrying specific mismatches (11, 12). On the other hand, p53 stimulates spontaneous HR during S-phase to overcome replication fork stalling and to pr...

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Section: Resultsmentioning

confidence: 99%

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

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

161

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“…Mitomycin C. Since the report by Iyer and Szybalski (1964), the requirement for redox biotransformation of mitomycin C (MMC) has been well recognized in pharmacology, because MMC must be activated by a series of redox reactions leading to semiquinone derivatives coupled with ROS formation (Dusre et al 1990;Gutteridge et al 1984;Penketh et al 2001;Pritsos and Sartorelli 1986). Well-established mechanistic information has shown that MMC-associated toxicity is dependent on oxygen levels (Clarke et al 1997;Korkina et al 2000) and is removed by low-molecularweight antioxidants (Raj and Heddle 1980) and by thioredoxin (Trx) overexpression (Ruppitsch et al 1998).…”

Section: Xenobiotics Involved In Defining Fa Phenotypementioning

confidence: 99%

Oxidative stress-related mechanisms are associated with xenobiotics exerting excess toxicity to Fanconi anemia cells.

Pagano¹,

Manini²,

Bagchi³

2003

Environ Health Perspect

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“…A salient feature of the molecular mechanism of action of MC is that this agent exists as a prodrug, and both its DNA crosslinking and monoalkylating activities require the reduction of the quinone ring to a hydroquinone, which transforms MC into a highly reactive alkylating species (11). Enzymes known to activate MC to intermediates capable of alkylating DNA do so either by a one-or a two-electron reduction mechanism.…”

mentioning

confidence: 99%

Nuclear Overexpression of NAD(P)H:Quinone Oxidoreductase 1 in Chinese Hamster Ovary Cells Increases the Cytotoxicity of Mitomycin C under Aerobic and Hypoxic Conditions

Seow¹,

Penketh²,

Belcourt³

et al. 2004

Journal of Biological Chemistry

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The effects of the subcellular localization of overexpressed bioreductive enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) on the activity of the antineoplastic agent mitomycin C (MC) under aerobic and hypoxic conditions were examined. Chinese hamster ovary (CHO-K1/ dhfr ؊ ) cells were transfected with NQO1 cDNA to produce cells that overexpressed NQO1 activity in the nucleus (148-fold) or the cytosol (163-fold) over the constitutive level of the enzyme in parental cells. Subcellular localization of the enzyme was confirmed using antibody-assisted immunofluorescence. Nuclear localization of transfected NQO1 activity increased the cytotoxicity of MC over that produced by overexpression in the cytosol under both aerobic and hypoxic conditions, with greater cytotoxicity being produced under hypoxia. The greater cytotoxicity of nuclear localized NQO1 was not attributable to greater metabolic activation of MC but instead was the result of activation of the drug in close proximity to its target, nuclear DNA. A positive relationship existed between the degree of MC-induced cytotoxicity and the number of MC-DNA adducts produced. The findings indicate that activation of MC proximal to nuclear DNA by the nuclear localization of transfected NQO1 increases the cytotoxic effects of MC regardless of the degree of oxygenation and support the concept that the mechanism of action of MC involves alkylation of DNA.Mitomycin C (MC) 1 is a naturally occurring antibiotic that was isolated originally from the microorganism Streptomyces caspitosus (1). MC exhibits a broad spectrum of antitumor activity and is an important component in the combination chemotherapy of malignancies such as early stage head and neck cancer, early stage cervical cancer, and intravesicle therapy of superficial bladder cancer. Specific MC-DNA lesions associated with the action of MC consist of both monofunctional and bifunctional alkylations (2-9). Monoalkylations initially occur through the linkage of the C-1 position of MC to the amino function in the 2-position of guanine bases in DNA and may proceed to a DNA cross-link through the C-10 position of MC to an amino entity in the 2-position of an adjacent DNA guanine (6). Although monoalkylations are potentially cytotoxic, compelling evidence in both bacterial and mammalian systems implicates MC-induced cross-links as the primary event responsible for cell death (10 -12).A salient feature of the molecular mechanism of action of MC is that this agent exists as a prodrug, and both its DNA crosslinking and monoalkylating activities require the reduction of the quinone ring to a hydroquinone, which transforms MC into a highly reactive alkylating species (11). Enzymes known to activate MC to intermediates capable of alkylating DNA do so either by a one-or a two-electron reduction mechanism. Oneelectron reducing enzymes include NADPH:cytochrome P450 oxidoreductase (NPR; EC 1.6.2.4) (13-16); NADH:cytochrome b 5 oxidoreductase (NBR; EC 1.6.2.2) (17, 18); xanthine:oxygen oxidoreductase (EC 1.1.3.23) (16); nitric-oxide s...

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Mitomycins and Porfiromycin: Chemical Mechanism of Activation and Cross-linking of DNA

Cited by 557 publications

References 11 publications

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Oxidative stress-related mechanisms are associated with xenobiotics exerting excess toxicity to Fanconi anemia cells.

Nuclear Overexpression of NAD(P)H:Quinone Oxidoreductase 1 in Chinese Hamster Ovary Cells Increases the Cytotoxicity of Mitomycin C under Aerobic and Hypoxic Conditions

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