Frameshifts and deletions during in vitro translesion synthesis past Pt–DNA adducts by DNA polymerases β and η

Bassett, Ekaterina; Vaisman, Alexandra; Tropea, Kristen A.; McCall, Chad M.; Masutani, Chikahide; Hanaoka, Fumio; Chaney, Stephen G.

doi:10.1016/s1568-7864(02)00150-7

Cited by 46 publications

(38 citation statements)

References 40 publications

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“…DNA replication continues even in the presence of DNA adducts leading to DNA translesion synthesis and to miscoding errors in the newly synthesised DNA [58]. Platinum-adducts may be successfully bypassed by translesional DNA polymerases [59] and several translesional DNA polymerases are capable of even bypassing platinum-adducts [22,60,61]. DNA polymerase β is able to synthesise DNA with greater efficiency in the presence of oxaliplatin adducts than those of cisplatin [57].…”

Section: Discussionmentioning

confidence: 99%

<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

Alotaibi¹,

Baumgartner²,

Najafzadeh³

et al. 2012

JCT

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Exposure to toxic chemicals, especially chemotherapeutic drugs, may induce several DNA lesions, including DNA interstrand crosslinks. These crosslinks are considered toxic lesions to the dividing cells since they can induce mutations, chromosomal rearrangements, and cell death. Many DNA interstrand crosslinks lesions can be generated by platinum-based chemotherapeutic agents. Satraplatin is a novel orally administered platinum-based chemotherapeutic agent. In the present study, we investigated DNA interstrand crosslinks lesions induced by oxaliplatin and satraplatin in lymphocytes obtained from colorectal cancer patients and healthy volunteers. Satraplatin demonstrated an increase in interstrand crosslinks in a dose-dependent manner in the Comet assay (p < 0.001). In addition, satraplatin and oxaliplatin increased significantly the number of sister chromatid exchanges up to 8.5-fold and 5.1-fold (p < 0.001) respectively, when treated with 2 µM concentration in comparison to untreated colorectal cancer cells. Further, the γH2AX foci formation was investigated by an immunofluorescence assay with oxaliplatin and satraplatin. The γH2AX foci formation rate was increased by approximately 9-fold when lymphocytes were treated with 2 μM oxaliplatin. Satraplatin was found to significantly induce the number of γH2AX foci by 8.5-fold and 11-fold with both 0.2 μM and 2.0 μM, respectively, compared to the control volunteers that may indicate the repair system in cancer cells experiences a loss of ability to cope with the repair of DSBs. In conclusion, oxaliplatin and satraplatin effectively induced DNA interstrand crosslinks in lymphocytes obtained from colorectal cancer patients and healthy volunteers in vitro. Here, to the best of our knowledge we report for the first time evidence of DNA double strand breaks formation as a possible molecular mechanism of action for satraplatin.

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Section: Discussionmentioning

confidence: 99%

<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

Alotaibi¹,

Baumgartner²,

Najafzadeh³

et al. 2012

JCT

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“…Thus, at least in some clinical settings, a high DNA repair capacity appears to protect against tumor relapse (Kamal et al, 2010) but may prevent patients to benefit from DNA-damaging agents. Of note, defects in MLH1 and MSH6 (another component of the MMR system) are associated with increased level of translesion synthesis, the phenomenon whereby DNA synthesis is not blocked but proceeds beyond cisplatin adducts (Bassett et al, 2002). Translesion synthesis, which is also known as replicative bypass, is mediated by the concerted activity of a specific group of DNA polymerases including POLH, POLI, POLK, REV1, REV3 and REV7 (Shachar et al, 2009).…”

Section: Mechanisms Of On-target Resistancementioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNAcisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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“…In addition, Pol D has been shown to bypass several other lesions, including O 4 -methyl thymine and O 6 -methyl guanine (15), adducts of acetylaminofluorene (11), adducts of cisplatin and oxaliplatin (11,16), and adducts of benzopyrenediolepoxide (17). Compared with predominantly correct incorporation opposite thymine dimers, Pol D frequently inserts incorrect nucleotides opposite some lesions [e.g., (+ and À)-trans-anti-BPDE-dG (17), AAF-dG (11), and both residues of a cisplatin cross-linked di-guanine adduct (11)], leading to the suggestion that TLS by Pol D could increase mutagenesis resulting from some types of environmental stress.…”

Section: Introductionmentioning

confidence: 99%

Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase η–deficient Mice

et al. 2006

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Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase H (pol h) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pol H to efficiently bypass UV light-induced cyclobutane pyrimidine dimers, XPV cells lacking Pol H have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light-induced killing and mutagenesis. To better understand these and other Pol H functions, we generated Pol H-deficient mice. Mice homozygous for a null mutation in pol h are viable, fertile, and do not show any obvious spontaneous defects during the first year of life. However, fibroblasts derived from these mutant mice are sensitive to killing by exposure to UV light, and all Pol H-deficient mice develop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did not develop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol H indicate that Pol H-dependent bypass of cyclobutane pyrimidine dimers suppresses UV light-induced skin cancer in mice. Moreover, 37.5% of pol h heterozygous mice also developed skin cancer during 5 months after a 5-month exposure to UV light, suggesting that humans who are heterozygous for mutations in pol h may also have an increased risk of skin cancer. (Cancer Res 2006; 66(1): 87-94)

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Frameshifts and deletions during in vitro translesion synthesis past Pt–DNA adducts by DNA polymerases β and η

Cited by 46 publications

References 40 publications

<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

Molecular mechanisms of cisplatin resistance

Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase η–deficient Mice

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Frameshifts and deletions during in vitro translesion synthesis past Pt–DNA adducts by DNA polymerases β and η

Cited by 46 publications

References 40 publications

&lt;i&gt;In Vitro&lt;/i&gt; Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

&lt;i&gt;In Vitro&lt;/i&gt; Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

Molecular mechanisms of cisplatin resistance

Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase η–deficient Mice

Contact Info

Product

Resources

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<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients