Replication-Fork Stalling and Processing at a Single Psoralen Interstrand Crosslink in Xenopus Egg Extracts

Breton, Cyrille Le; Hennion, Magali; Arimondo, Paola B.; Hyrien, Olivier

doi:10.1371/journal.pone.0018554

Cited by 16 publications

(15 citation statements)

References 44 publications

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“…Chk1 inhibition is implicated in the recapitulation of S-phase progression of cells after treatment with agents, such as camptothecin and IR, as it is activated by stalled DNA replication forks (13, 22, 34, 45). Moreover, inhibition of the ATR-Chk1 pathway has been shown to slowdown fork breakage and repair after inter-strand cross-linking (47). AZD7762 increases the origin firing in HCT116 cells, by itself and also when treated with gemcitabine (29).…”

Section: Discussionmentioning

confidence: 99%

Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor AZD7762

Aris

Pommier

2012

Cancer Research

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Novel topoisomerase I (Top1) inhibitors are in clinical development to circumvent the drawbacks of camptothecins. Here we report molecular investigations into LMP-400, an indenoisoquinoline Top1 inhibitor in Phase 1 clinical trial, by itself and in combination with the cell cycle checkpoint inhibitor, AZD7762. We examined drug effects on DNA replication and killing of cancer cells and found that LMP-400 showed synergistic antiproliferative activity when combined with AZD7762 in human colon carcinoma cells. Inhibition of S-phase progression and bromodeoxyuridine incorporation were similarly induced by LMP-400 and camptothecin (CPT) and were abrogated by AZD7762. Replication studied by single DNA molecule analyses and immunofluorescence microscopy (molecular combing) showed rapid inhibition of fork progression in response to LMP-400 treatment with subsequent recapitulation after AZD7762 addition. AZD7762 inhibited both the activation/autophosphosphorylation of Chk1 and Chk2 at nanomolar concentrations in LMP-400-treated cells. This potent dual inhibition of Chk1 and Chk2 by AZD7762 was below the drug concentrations required to abrogate cell cycle inhibition and produce synergism with LMP-400. Also, the synergism was independent of Chk2 both in Chk2-complemented cells and Chk2 knockout cells, suggesting additional mechanisms for cell cycle abrogation by AZD7762. Together, our findings demonstrate a rationale for combining cell cycle checkpoint inhibitors with the novel non-camptothecin indenoisoquinoline Top1 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor AZD7762

Aris

Pommier

2012

Cancer Research

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“…Replication of a psoralen ICL in Xenopus egg extracts suggested that sometimes, a single fork can trigger incisions, but it was unclear whether the observed incisions led to a productive repair outcome (Le Breton et al, 2011). In mammalian cells, repair of an ICL flanked by a replication roadblock suggested that a single fork can trigger repair (Nakanishi et al, 2011).…”

Section: Can a Single Fork Trigger Icl Repair?mentioning

confidence: 99%

Mechanism and regulation of incisions during DNA interstrand cross-link repair

2014

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A critical step in DNA interstrand cross-link repair is the programmed collapse of replication forks that have stalled at an ICL. This event is regulated by the Fanconi anemia pathway, which suppresses bone marrow failure and cancer. In this perspective, we focus on the structure of forks that have stalled at ICLs, how these structures might be incised by endonucleases, and how incision is regulated by the Fanconi anemia pathway.

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“…FA proteins participate in unhooking, as well as bypass replication across the crosslink remnant (Knipscheer et al, 2009; Long et al, 2011). In another study, also with Xenopus egg extracts and plasmids, both single and double fork collisions were observed (Le et al, 2011). …”

Section: Introductionmentioning

confidence: 96%

The DNA Translocase FANCM/MHF Promotes Replication Traverse of DNA Interstrand Crosslinks

et al. 2013

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SUMMARY The replicative machinery encounters many impediments, some of which can be overcome by lesion bypass or replication restart pathways, leaving repair for a later time. However, interstrand crosslinks (ICLs), which preclude DNA unwinding, are considered absolute blocks to replication. Current models suggest that fork collisions, either from one or both sides of an ICL, initiate repair processes required for resumption of replication. To test these proposals, we developed a single molecule technique for visualizing encounters of replication forks with ICLs, as they occur in living cells. Surprisingly, the most frequent patterns were consistent with replication traverse of an ICL, without lesion repair. The traverse frequency was strongly reduced by inactivation of the translocase and DNA binding activities of the FANCM/MHF complex. The results indicate that translocase-based mechanisms enable DNA synthesis to continue past ICLs, and that these lesions are not always absolute blocks to replication.

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Replication-Fork Stalling and Processing at a Single Psoralen Interstrand Crosslink in Xenopus Egg Extracts

Cited by 16 publications

References 44 publications

Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor AZD7762

Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor AZD7762

Mechanism and regulation of incisions during DNA interstrand cross-link repair

The DNA Translocase FANCM/MHF Promotes Replication Traverse of DNA Interstrand Crosslinks

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