Triplex targeted genomic crosslinks enter separable deletion and base substitution pathways

Richards, Sally; Liu, Su-Ting; Majumdar, Angshuman; Liu, Ji-Lan; Nairn, Rodney S.; Bernier, Michel; Maher, Veronica M.; Seidman, Michael M.

doi:10.1093/nar/gki851

Cited by 36 publications

(51 citation statements)

References 74 publications

(108 reference statements)

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“…Our work in human cells corroborates and complements prior work, all in Chinese hamster ovary cells, demonstrating that ERCC1, which normally is in a heterodimeric complex with XPF, is required for the initial incisions and γ-H2AX formation [32], and that XPF and ERCC1 are required for incisions leading to DSB in an in vitro assay [14]. Our results are also consistent with the finding that XPF loss suppresses sister chromatid exchange following mitomycin C treatment [49], as well as with models in which the ICL-specific 5′ and 3′ endonuclease activities of the XPF-ERCC1 complex are a relatively early event preceding and required for DSB formation [25,32,50]. Although cell extracts have been reported to make dual incisions 5′ to a psoralen ICL, one of which was dependent on XPF, no DSB occurred as a result of this reaction, and thus these types of incisions alone do not explain the dependence of DSB formation on XPF [51].…”

Section: Discussionsupporting

confidence: 89%

“…Cisplatin forms a small number of ICL and fails to induce DSB in rodent cells [48]. NER processing of psoralen ICL that depends on XPA and other NER proteins to uncouple one strand of the ICL [21,22], followed by translesion synthesis with a bypass polymerase may be one scenario that could account for reduced DSB formation in GM637 cells relative to XP-A cells [11,20,50,51].…”

Section: Discussionmentioning

confidence: 99%

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γ-H2AX formation in response to interstrand crosslinks requires XPF in human cells

Mogi

2006

DNA Repair

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To further define the molecular mechanisms involved in processing interstrand crosslinks, we monitored the formation of phosphorylated histone H2AX (γ-H2AX), which is generated in chromatin near double strand break sites, following DNA damage in normal and repair-deficient human cells. Following treatment with a psoralen derivative and ultraviolet A radiation doses that produce significant numbers of crosslinks, γ-H2AX levels in nucleotide excision repair-deficient XP-A fibroblasts (XP12RO-SV) increased to levels that were twice those observed in normal control GM637 fibroblasts. A partial XPA revertant cell line (XP129) that is proficient in crosslink removal, exhibited reduced γ-H2AX levels that were intermediate between those of GM637 and XP-A cells. XP-F fibroblasts (XP2YO-SV and XP3YO) that are also repair-deficient exhibited γ-H2AX levels below even control fibroblasts following treatment with psoralen and ultraviolet A radiation. Similarly, another crosslinking agent, mitomycin C, did not induce γ-H2AX in XP-F cells, although it did induce equivalent levels of γ-H2AX in XPA and control GM637 cells. Ectopic expression of XPF in XP-F fibroblasts restored γ-H2AX induction following treatment with crosslinking agents. Angelicin, a furocoumarin which forms only monoadducts and not crosslinks following ultraviolet A radiation, as well as ultraviolet C radiation, resulted only in weak induction of γ-H2AX in all cells, suggesting that the double strand breaks observed with psoralen and ultraviolet A treatment result preferentially following crosslink formation. These results indicate that XPF is required to form γ-H2AX and likely double strand breaks in response to interstrand crosslinks in human cells. Furthermore, XPA may be important to allow psoralen interstrand crosslinks to be processed without forming a double strand break intermediate.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

γ-H2AX formation in response to interstrand crosslinks requires XPF in human cells

Mogi

2006

DNA Repair

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“…Recent studies have suggested that polymerase ζ is the predominant determinant of ICL repair [14][15][16]. However, in yeast, REV3 activity in ICL repair was restricted exclusively to the G1 phase of the cell cycle, leaving open the possibility that other TLS polymerases might fulfill similar roles in other phases of the cell cycle [15].…”

Section: Discussionmentioning

confidence: 99%

“…Several reports have indicated that TLS by polymerase ζ plays a key role in repairing ICL [11,[14][15][16]. However, another polymerase involved in TLS, polymerase η (pol η), has also been variably implicated in ICL repair.…”

Section: Introductionmentioning

confidence: 99%

DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

Mogi

Butcher

2008

Experimental Cell Research

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DNA interstrand crosslinks are processed by multiple mechanisms whose relationships to each other are unclear. Xeroderma pigmentosum-variant (XP-V) cells lacking DNA polymerase η are sensitive to psoralen photoadducts created under conditions favoring crosslink formation, suggesting a role for translesion synthesis in crosslink repair. Because crosslinks can lead to double strand breaks, we monitored phosphorylated H2AX (γ-H2AX), which is typically generated near double-strand breaks but also in response to single-stranded DNA, following psoralen photoadduct formation in XP-V fibroblasts to assess whether polymerase η is involved in processing crosslinks. In contrast to conditions favoring monoadducts, conditions favoring psoralen crosslinks induced γ-H2AX levels in both XP-V and nucleotide excision repair-deficient XP-A cells relative to control repair-proficient cells; ectopic expression of polymerase η in XP-V cells normalized the γ-H2AX response. In response to psoralen crosslinking, γ-H2AX as well as 53BP1 formed co-incident foci that were more numerous and intense in XP-V and XP-A cells than in controls. Psoralen photoadducts induced γ-H2AX throughout the cell cycle in XP-V cells. These results indicate that polymerase η is important in responding to psoralen crosslinks, and are consistent with a model in which nucleotide excision repair and polymerase η are involved in processing crosslinks and avoiding γ-H2AX associated with double strand breaks and single-stranded DNA in human cells.

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“…Further support for involvement of pol and another TLS polymerase, Rev1, in tolerance to ICL damage and their contribution to ICL-associated mutagenesis was obtained in both yeast (7,12) and vertebrate cells (6,8,13).…”

mentioning

confidence: 87%

Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links

Minko

Harbut

Kozekov

et al. 2008

Journal of Biological Chemistry

122

187

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Although there exists compelling genetic evidence for a homologous recombination-independent pathway for repair of interstrand cross-links (ICLs) involving translesion synthesis (TLS), biochemical support for this model is lacking. To identify DNA polymerases that may function in TLS past ICLs, oligodeoxynucleotides were synthesized containing site-specific ICLs in which the linkage was between N 2 -guanines, similar to crosslinks formed by mitomycin C and enals. Here, data are presented that mammalian cell replication of DNAs containing these lesions was ϳ97% accurate. Using a series of oligodeoxynucleotides that mimic potential intermediates in ICL repair, we demonstrate that human polymerase (pol) not only catalyzed accurate incorporation opposite the cross-linked guanine but also replicated beyond the lesion, thus providing the first biochemical evidence for TLS past an ICL. The efficiency of TLS was greatly enhanced by truncation of both the 5 and 3 ends of the nontemplating strand. Further analyses showed that although yeast Rev1 could incorporate a dCTP opposite the cross-linked guanine, no evidence was found for TLS by pol or a pol /Rev1 combination. Because pol was able to bypass these ICLs, biological evidence for a role for pol in tolerating the N 2 -N 2 -guanine ICLs was sought; both cell survival and chromosomal stability were adversely affected in pol -depleted cells following mitomycin C exposure. Thus, biochemical data and cellular studies both suggest a role for pol in the processing of N 2 -N 2 -guanine ICLs.

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Triplex targeted genomic crosslinks enter separable deletion and base substitution pathways

Cited by 36 publications

References 74 publications

γ-H2AX formation in response to interstrand crosslinks requires XPF in human cells

γ-H2AX formation in response to interstrand crosslinks requires XPF in human cells

DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links

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