DNA Interstrand Crosslinks: Natural and Drug‐Induced DNA Adducts that Induce Unique Cellular Responses

Schärer, Orlando D.

doi:10.1002/cbic.200400287

Cited by 174 publications

(191 citation statements)

References 67 publications

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“…Perhaps limited ICLs or other DNA lesions that lead to replication stalling are contributing factors to such ATM-independent DNA damage responses. Furthermore, ATR's late regulation of DNA damage responses to treatments inducing primarily DSBs (8,19) would be consistent with the typically slower induction kinetics for ICLs than DSBs (15,20). Finally, similar to calicheamicin at elevated levels, we also have observed that, at high drug concentrations, deschloro, deshydroxy, and neocarzinostatin activate ATMindependent damage responses (T.A.B., unpublished data).…”

Section: Discussionsupporting

confidence: 71%

Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses

Kennedy

Shen

et al. 2007

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

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The ability of the radiomimetic anticancer enediyne C-1027 to induce ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR)-independent damage responses was discovered to reside in its unique ability to concurrently generate robust amounts of double-strand breaks (DSBs) and interstrand cross-links (ICLs) in cellular DNA. Furthermore, a single substitution to the chromophore's benzoxazolinate moiety shifted DNA damage to primarily ICLs and an ATR-but not ATM-dependent damage response. In contrast, single substitutions of the chromophore's ␤-amino acid component shifted DNA damage to primarily DSBs, consistent with its induction of conventional ATM-dependent damage responses of the type generated by ionizing radiation and other radiomimetics. Thus, phosphatidylinositol 3-kinase-like protein kinase regulation of DNA damage responses is dictated by the relative proportions of DSBs and ICLs.DNA double-strand break ͉ C-1027 ͉ radioimetic ͉ ATM ͉ ATR C ells use several members of phosphatidylinositol 3-kinaselike protein kinases (PIKKs), including ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR), to initiate cell cycle checkpoint responses to DNA damage (1). The induction of double-strand breaks (DSBs) into cellular DNA rapidly triggers ATM activation, which promotes a kinase cascade involving phosphorylation of the signal transducers Chk1 and Chk2 and downstream targets such as p53, all of which contribute to cell cycle arrest (1, 2). Similar to ATM, ATR activates Chk1, p53, and, to a lesser degree, Chk2 to initiate cell cycle checkpoints in response to lesions such as interstrand cross-links (ICLs), which stall DNA replication (2).Although ATM's role in responding to DSBs was primarily based on ionizing radiation (IR) studies, radiomimetic enediynes such as neocarzinostatin, C-1027, and calicheamicin also have provided insight (3). Enediynes are a structurally diverse group of compounds whose chromophores bind to the DNA minor groove and subsequently undergo Bergman cycloaromatization, generating two free radicals (4, 5). These radicals can induce DSBs when hydrogen atoms in close proximity, but on opposite DNA strands (6), are abstracted from deoxyribose.Cellular responses to radiomimetic treatment are similar to IR, which include ATM-dependent activation of p53-Ser-15 and Chk2-Thr-68 (7, 8) and enhanced cell death in cells lacking ATM (5). That responses to DSBs are ATM-dependent regardless of the damaging agent has led to the general conclusion that cells require ATM to activate DNA damage responses to DSBs (5, 6). The sole exception is C-1027, where cells deficient in either ATM or ATR phosphorylate p53-Ser-15 and Chk2-Thr-68 as readily as wild type and are diminished only when both PIKKs are absent (9, 10). Furthermore, C-1027 is similarly toxic to wild-type, ATM-, or ATR-deficient cells, because cell death hypersensitivity occurs only in the absence of both (10).Remarkably, minor modifications of the C-1027 chromophore can alter the PIKK dependence of the DNA damage response (11). ...

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Section: Discussionsupporting

confidence: 71%

Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses

Kennedy

Shen

et al. 2007

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

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“…In particular, CTX is the front-line treatment for a wide range of lymphoma subtypes, either as a single agent or in combination with other chemotherapeutics. CTX is a nitrogen mustard alkylating agent that, like cisplatin, forms highly toxic intrastrand crosslinks between guanine nucleotides that impede normal DNA replication (21)(22)(23). We chose to evaluate the role of Rev1 in mediating the response of our lymphoma cells to CTX (i) because of its central role in mutagenesis (3, 9), (ii) because of its key role in interacting with Polζ and other TLS DNA polymerases (3,17,18), and (iii) because it has been implicated in the replication-dependent repair of a nitrogen-mustard-like interstrand crosslink in a Xenopus cell-free system (24).…”

Section: Resultsmentioning

confidence: 99%

Error-prone translesion synthesis mediates acquired chemoresistance

Xie¹,

Doles

Hemann

et al. 2010

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

187

207

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The development of cancer drug resistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. Error-prone translesional DNA synthesis (TLS) is known to underlie the mutagenic effects of numerous anticancer agents, but little is known as to whether mutation induced by this process is ultimately relevant to tumor drug resistance. Here, we use a tractable mouse model of B-cell lymphoma to interrogate the role of error-prone translesional DNA synthesis in chemotherapyinduced mutation and resistance to front-line chemotherapy. We find that suppression of Rev1, an essential TLS scaffold protein and dCMP transferase, inhibits both cisplatin-and cyclophosphamideinduced mutagenesis. Additionally, by performing repeated cycles of tumor engraftment and treatment, we show that Rev1 plays a critical role in the development of acquired cyclophosphamide resistance. Thus, chemotherapy not only selects for drug-resistant tumor population but also directly promotes the TLS-mediated acquisition of resistance-causing mutations. These data provide an example of an alteration that prevents the acquisition of drug resistance in tumors in vivo. Because TLS also represents a critical mechanism of DNA synthesis in tumor cells following chemotherapy, these data suggest that TLS inhibition may have dual anticancer effects, sensitizing tumors to therapy as well as preventing the emergence of tumor chemoresistance.DNA polymerase | cancer | chemotherapy | relapse T he development of acquired chemoresistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. Tumors that relapse following initial treatment frequently are refractory to subsequent administration of the initial drug regimen as well as to distinct sets of chemotherapeutics. Although a number of key pathways have been implicated in resistance to conventional chemotherapeutics, including enhanced drug efflux, increased drug metabolism, drug inactivation, enhanced DNA repair, and defects in apoptosis programs (1, 2), the mechanisms by which tumors develop drug resistance-causing mutations remains unclear.At its core, acquired chemoresistance represents the emergence of subpopulations of drug-resistant tumor cells, a phenomenon rooted in the inherent genetic heterogeneity of the tumor itself. This heterogeneity may occur as a consequence of tumor genetic instability, a process known to underlie tumor development in numerous malignancies. Alternatively, cancer therapy itself may promote mutation and subsequent chemoresistance in relapsed tumors. Support for the latter hypothesis comes from several observations. First, conventional chemotherapeutics can be highly mutagenic (3). In fact, considerable work has gone into highlighting the mutagenic properties of platinum-based and other DNA adduct-forming chemotherapeutics as well as the genes that act in the cellular res...

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“…These lesions are located one or two nucleotides apart on the opposite strands and covalently link them, blocking DNA replication and transcription (1)(2)(3). Therefore, ICLs are considered to be the most cytotoxic DNA lesion (2)(3)(4).…”

Section: Dna Interstrand Cross-links (Icls)mentioning

confidence: 99%

Processing of a Psoralen DNA Interstrand Cross-link by XPF-ERCC1 Complex in Vitro

Fisher

Bessho

2008

Journal of Biological Chemistry

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The processing of stalled forks caused by DNA interstrand cross-links (ICLs) has been proposed to be an important step in initiating mammalian ICL repair. To investigate a role of the XPF-ERCC1 complex in this process, we designed a model substrate DNA with a single psoralen ICL at a three-way junction (Y-shaped DNA), which mimics a stalled fork structure. We found that the XPF-ERCC1 complex makes an incision 5 to a psoralen lesion on Y-shaped DNA in a damage-dependent manner. Furthermore, the XPF-ERCC1 complex generates an ICLspecific incision on the 3-side of an ICL. The ICL-specific 3-incision, along with the 5-incision, on the cross-linked Y-shaped DNA resulted in the separation of the two cross-linked strands (the unhooking of the ICL) and the induction of a double strand break near the cross-linked site. These results implicate the XPF-ERCC1 complex in initiating ICL repair by unhooking the ICL, which simultaneously induces a double strand break at a stalled fork. DNA interstrand cross-links (ICLs)2 are formed as a result of DNA damage to each strand of the duplex. These lesions are located one or two nucleotides apart on the opposite strands and covalently link them, blocking DNA replication and transcription (1-3). Therefore, ICLs are considered to be the most cytotoxic DNA lesion (2-4).Several models for mammalian ICL repair have been proposed (2, 5-7). The first critical step for repairing ICLs in any given model is to release the ICL from one of the strands by making two incisions that bracket an ICL (unhooking the ICL). The unhooking of ICLs permits strand separation. In Escherichia coli and yeast, nucleotide excision repair (NER) makes dual incisions bracketing the ICL on one of the cross-linked strands to unhook ICLs (2, 3). Interestingly, NER is dispensable in mammalian ICL repair (5,8). In contrast to NER-defective mutants in E. coli and yeast, the NER-defective mammalian cells (except for ERCC-1 and ERCC-4 cells) are only moderately sensitive to DNA cross-linking agents such as mitomycin C (MMC) (8 -11). Moreover, biochemical studies demonstrated that the dual incisions by mammalian NER do not "unhook" ICLs (12, 13). Therefore, mammalian cells evidently have a unique mechanism(s) to initiate ICL repair.Notably, double strand break (DSB) repair-defective mutant cells, including those deficient in Rad51 paralogs or BRCA2, are hypersensitive to DNA cross-linking agents such as MMC (10). It has also been reported that ICLs in the mammalian genome are removed during S-phase and the DNA replication-mediated formation of a DSB is the key intermediate in ICL repair in mammalian cells (1,8,14,15). These data indicate that mammalian ICL repair goes through three critical processes: the formation of DNA replication-mediated DSBs, unhooking of the ICLs (separation of the two linked strands), and repair of the DSBs (restoration of the collapsed replication fork). It is unknown whether the formation of DSBs precedes the unhooking reaction. When the DNA replication complex encounters an ICL, the strand separat...

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DNA Interstrand Crosslinks: Natural and Drug‐Induced DNA Adducts that Induce Unique Cellular Responses

Cited by 174 publications

References 67 publications

Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses

Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses

Error-prone translesion synthesis mediates acquired chemoresistance

Processing of a Psoralen DNA Interstrand Cross-link by XPF-ERCC1 Complex in Vitro

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