Formation and stability of interstrand cross-links induced by cis- and trans-diamminedichloroplatinum (II) in the DNA of Saccharomyces cerevisiae strains differing in repair capacity

Wilborn, Freimut; Brendel, Martin

doi:10.1007/bf00340711

Cited by 41 publications

(29 citation statements)

References 39 publications

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“…The antitumor agents nitrogen mustard (HN2) and cisplatin have been the subjects of a number of previous studies with S. cerevisiae that have attempted to elucidate the DNA repair pathways acting on the DNA ICLs they produce (8,55,65). For HN2 it is notable that all these studies conclude that NER and members of the RAD6 epistasis group (RAD18 and REV3) are important in the repair of ICLs (52) whereas recombination, as mediated by RAD52 pathway, is not (55).…”

Section: Discussionmentioning

confidence: 99%

“…Both these agents produce ICLs as only a fraction of the total damage (10% or less) (15,26), but in both cases it is known that NER is required for the early steps of repair (8,65). It is clear that in a rapidly dividing (exponential-phase) culture there is a requirement for recombination, but this is abolished in stationary-phase cultures (where cells are not dividing) and a REV3 dependent mutagenic pathway is used instead.…”

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confidence: 99%

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Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

McHugh

Sones

Hartley

2000

Molecular and Cellular Biology

143

152

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Bifunctional alkylating agents and other drugs which produce DNA interstrand cross-links (ICLs) are among the most effective antitumor agents in clinical use. In contrast to agents which produce bulky adducts on only one strand of the DNA, the cellular mechanisms which act to eliminate DNA ICLs are still poorly understood, although nucleotide excision repair is known to play a crucial role in an early repair step. Using haploid Saccharomyces cerevisiae strains disrupted for genes central to the recombination, nonhomologous end-joining (NHEJ), and mutagenesis pathways, all these activities were found to be involved in the repair of nitrogen mustard (mechlorethamine)-and cisplatin-induced DNA ICLs, but the particular pathway employed is cell cycle dependent. Examination of whole chromosomes from treated cells using contour-clamped homogenous electric field electrophoresis revealed the intermediate in the repair of ICLs in dividing cells, which are mostly in S phase, to be double-strand breaks (DSBs). The origin of these breaks is not clear since they were still efficiently induced in nucleotide excision and base excision repair-deficient, mismatch repair-defective, rad27 and mre11 disruptant strains. In replicating cells, RAD52-dependent recombination and NHEJ both act to repair the DSBs. In contrast, few DSBs were observed in quiescent cells, and recombination therefore seems dispensable for repair. The activity of the Rev3 protein (DNA polymerase ) is apparently more important for the processing of intermediates in stationary-phase cells, since rev3 disruptants were more sensitive in this phase than in the exponential growth phase.Many clinically important anticancer drugs such as those from the nitrogen mustard class, as well as many agents in development, exert their antitumor effects through the production of DNA interstrand cross-links (ICLs) (26,47). Agents such as cisplatin can also produce ICLs, but intrastrand adducts may also contribute to cytotoxicity (15). It is well established that nucleotide excision repair (NER) plays a key early role in the repair of ICLs (3,8,27,37,39), but little is known about the nature of the incisions at these lesions, the resulting repair intermediates, and how they are resolved. The NER pathway acting on DNA intrastrand cross-links (e.g., UV-induced dipyrimidine photoproducts and the intrastrand crosslinks produced by cisplatin) in eukaryotes is well understood (22); excision of a 24-to 32-mer lesion-containing oligonucleotide is followed by repair synthesis and ligation. However, ICLs pose a unique problem because a one-step NER reaction releasing the DNA-drug adduct on one side of the cross-link leaves an oligonucleotide-drug moiety attached to the complementary strand. Since this will act as a block to DNA polymerases, the resynthesis-ligation portion of the NER reaction cannot proceed efficiently.It has been suggested that the information necessary to complete repair can be obtained by recombination with a sister chromatid or homolog (32) or by mutagenic DNA synthesis...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

McHugh

Sones

Hartley

2000

Molecular and Cellular Biology

143

152

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“…The molecular function of yeast Snm1 remains poorly defined. Mutants of snm1/ pso2 appear normal in the initial processing steps of interstrand cross-link (ICL) repair, but are defective in the resolution of double-strand breaks (DSBs) that occur presumably as a consequence of replication fork collapse in response to ICLs (Magana-Schwencke et al, 1982;Wilborn and Brendel, 1989;Li and Moses, 2003;Barber et al, 2005). Interestingly, Snm1 has been shown to have an overlapping role with the 5 0 -3 0 mismatch repair exonuclease Exo1 during processing of collapsed replication forks via homologous recombination (Barber et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links

et al. 2008

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The removal of DNA interstrand cross-links (ICLs) has proven to be notoriously complicated due to the involvement of multiple pathways of DNA repair, which include the Fanconi anemia/BRCA pathway, homologous recombination and components of the nucleotide excision and mismatch repair pathways. Members of the SNM1 gene family have also been shown to have a role in mediating cellular resistance to ICLs, although their precise function has remained elusive. Here, we show that knockdown of Snm1B/Apollo in human cells results in hypersensitivity to mitomycin C (MMC), but not to IR. We also show that Snm1B-deficient cells exhibit a defective S phase checkpoint in response to MMC, but not to IR, and this finding may account for the specific sensitivity to the cross-linking drug. Interestingly, although previous studies have largely implicated ATR as the major kinase activated in response to ICLs, we show that it is activation of the ATMmediated checkpoint that is defective in Snm1B-deficient cells. The requirement for Snm1B in ATM checkpoint activation specifically after ICL damage is correlated with its role in promoting double-strand break formation, and thus replication fork collapse. Consistent with this result Snm1B was found to interact directly with Mus81-Eme1, an endonuclease previously implicated in fork collapse. In addition, we also show that Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein.

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“…The interdependence between unhooking and formation of DSBs remains unclear (7). Yeast snm1 mutants are proficient in unhooking but are unable to process DSB intermediates (7,19,40).In mammalian cells, the situation is even more complex.Among NER factors, XPF/ERCC1 endonuclease appears to be particularly important for the unhooking of ICLs (5,21,26,32). Hamster mutant cells lacking the RAD51 paralog XRCC2 or XRCC3 display extreme sensitivity to ICLs, indicating an important role of HR in mammalian ICL repair (17).…”

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confidence: 99%

“…The interdependence between unhooking and formation of DSBs remains unclear (7). Yeast snm1 mutants are proficient in unhooking but are unable to process DSB intermediates (7,19,40).…”

mentioning

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DNA Cross-Link Repair Protein SNM1A Interacts with PIAS1 in Nuclear Focus Formation

Ishiai

Kimura

Namikoshi

et al. 2004

Molecular and Cellular Biology

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The yeast SNM1/PSO2 gene specifically functions in DNA interstrand cross-link (ICL) repair, and its role has been suggested to be separate from other DNA repair pathways. In vertebrates, there are three homologs of SNM1 (SNM1A, SNM1B, and SNM1C/Artemis; SNM1 family proteins) whose functions are largely unknown. We disrupted each of the SNM1 family genes in the chicken B-cell line DT40. Both SNM1A-and SNM1B-deficient cells were sensitive to cisplatin but not to X-rays, whereas SNM1C/Artemis-deficient cells exhibited sensitivity to X-rays but not to cisplatin. SNM1A was nonepistatic with XRCC3 (homologous recombination), RAD18 (translesion synthesis), FANCC (Fanconi anemia), and SNM1B in ICL repair. SNM1A protein formed punctate nuclear foci depending on the conserved SNM1 (metallo-␤-lactamase) domain. PIAS1 was found to physically interact with SNM1A, and they colocalized at nuclear foci. Point mutations in the SNM1 domain, which disrupted the interaction with PIAS1, led to mislocalization of SNM1A in the nucleus and loss of complementation of snm1a cells. These results suggest that interaction between SNM1A and PIAS1 is required for ICL repair.DNA interstrand cross-links (ICLs) covalently bind the two complementary strands of the double helix of DNA. They severely impair fundamental processes of DNA metabolism such as transcription or replication, leading to cell death if they are left unrepaired. Current protocols for cancer chemotherapy often include ICL-inducing agents, i.e., mitomycin C (MMC) or cisplatin, for effective killing of malignant cells (reviewed in references 7 and 21).The molecular mechanism of ICL repair is still poorly understood. In the yeast Saccharomyces cerevisiae, three distinct pathways, including nucleotide excision repair (NER), homologous recombination (HR), and translesion synthesis (TLS), participate in ICL repair (7,20). In addition, yeast SNM1 (also known as PSO2) specifically functions in ICL repair without apparently participating directly in any of these pathways (2, 9). During the repair process, NER mediates incisions on both sides of the cross-linked DNA (sometimes termed "unhooking") (5), and double-strand breaks (DSBs), which are probably associated with the collapse of a replication fork, are formed. The DSBs are then repaired by HR mechanisms. The interdependence between unhooking and formation of DSBs remains unclear (7). Yeast snm1 mutants are proficient in unhooking but are unable to process DSB intermediates (7,19,40).In mammalian cells, the situation is even more complex.Among NER factors, XPF/ERCC1 endonuclease appears to be particularly important for the unhooking of ICLs (5,21,26,32). Hamster mutant cells lacking the RAD51 paralog XRCC2 or XRCC3 display extreme sensitivity to ICLs, indicating an important role of HR in mammalian ICL repair (17). Cells from Fanconi anemia (FA) patients are also highly sensitive to ICL reagents (33), but the role of FA proteins in ICL repair is still unclear (4). Furthermore, there are three homologs of SNM1 (referred to as SNM1A, S...

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Formation and stability of interstrand cross-links induced by cis- and trans-diamminedichloroplatinum (II) in the DNA of Saccharomyces cerevisiae strains differing in repair capacity

Cited by 41 publications

References 39 publications

Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

Repair of Intermediate Structures Produced at DNA Interstrand Cross-Links in Saccharomyces cerevisiae

Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links

DNA Cross-Link Repair Protein SNM1A Interacts with PIAS1 in Nuclear Focus Formation

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