Initiation of DNA Interstrand Cross-Link Repair in Humans: the Nucleotide Excision Repair System Makes Dual Incisions 5′ to the Cross-linked Base and Removes a 22- to 28-Nucleotide-long Damage-Free Strand

Bessho, Tadayoshi; Mu, David; Sancar, Aziz

doi:10.1128/mcb.17.12.6822

Cited by 123 publications

(114 citation statements)

References 64 publications

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“…To explore the origin of the DSBs, their induction in exponentially growing HN2-treated NER disruptant strains was assessed, since available information suggests that this is the pathway which initiates ICL repair (6,29,39). Surprisingly, isogenic disruptant rad4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We sought to address the reasons for this discrepancy, particularly because existing models of ICL repair generally demand a role for recombination (6,12). Our data clearly show that rad52 sensitivity to HN2 and cisplatin is dependent upon growth phase, with recombination being required only during exponential-phase repair.…”

Section: Discussionmentioning

confidence: 99%

“…Bessho et al (6) have previously highlighted the reasons why conventional NER models might be inadequate to account for the repair of ICLs, since they require that a "bubble" be unwound around the lesion prior to incision. Such a step may be blocked by an ICL.…”

mentioning

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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Thus, there is a correlation between the preferred cross-link sequence, structural data, and a subset of the observed mutation spectrum (57). MDA-induced mutations at sites other than 5Ј-(CG) may have arisen as a result of NER-dependent incision of sequences flanking the 5Ј-(CG) ICLs (59,60), through the intermediacy of cross-links at other sequences, or from other MDA-DNA adducts that trigger mutations in an NER-dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells

Niedernhofer

Daniels

Rouzer

et al. 2003

Journal of Biological Chemistry

484

324

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“…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.…”

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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Initiation of DNA Interstrand Cross-Link Repair in Humans: the Nucleotide Excision Repair System Makes Dual Incisions 5′ to the Cross-linked Base and Removes a 22- to 28-Nucleotide-long Damage-Free Strand

Cited by 123 publications

References 64 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

Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells

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

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