DNA interstrand crosslink repair and cancer

Deans, Andrew J.; West, Stephen C.

doi:10.1038/nrc3088

Cited by 873 publications

(896 citation statements)

References 159 publications

(154 reference statements)

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“…Thus, depletion of FA core proteins can trigger uncontrolled resection of DNA. 19,33 In particular, isolated depletion of FancD2 is known to induce over-resection of DNA by the helicase/nuclease DNA2 (albeit not chromosome condensation). 33 Thus, we tested whether DNA2 knockdown could overcome chromosome fragmentation in ganetespib/carboplatin-treated ovarian cancer cells.…”

Section: Carbomentioning

confidence: 99%

“…17 Platinum compounds form intrastrand DNA lesions but also interstrand crosslinks (ICLs) by covalently linking opposite DNA strands. Such ICLs represent major obstacles to the DNA replication fork 19 and are therefore considered the principal toxic lesion of carboplatin's mode of action. The ICLs can only be removed by a sophisticated DNA repair systemthe Fanconi Anemia pathway (FA) -which consists of numerous protein components acting within complexes.…”

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confidence: 99%

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Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation. Live-cell microscopy revealed chromosome fragmentation occurring to a dramatic degree when cells condensed their chromatin in preparation for mitosis, followed by cell death in mitosis or upon aberrant exit from mitosis. HSP90 inhibition caused the rapid decay of key components of the Fanconi anemia pathway required for repair of carboplatin-induced interstrand crosslinks (ICLs), as well as of cell cycle checkpoint mediators. Overexpressing FancA rescued the DNA damage induced by the drug combination, indicating that FancA is indeed a key client of Hsp90 that enables cancer cell survival in the presence of ICLs. Conversely, depletion of nuclease DNA2 prevented chromosomal fragmentation, pointing to an imbalance of defective repair in the face of uncontrolled nuclease activity as mechanistic basis for the observed premitotic DNA fragmentation. Importantly, the drug combination induced robust antitumor activity in xenograft models, again accompanied with depletion of FancA. In sum, our findings indicate that ganetespib strongly potentiates the antitumor efficacy of carboplatin by causing combined inhibition of DNA repair and cell cycle control mechanisms, thus triggering global chromosome disruption, aberrant mitosis and cell death. 6 This provides a strong rationale for HSP90 inhibitors in cancer therapy 7 and raises the possibility that HSP90 inhibitors can be used in combination with DNAdamaging chemotherapeutics. 8 Ovarian cancer is among the most common gynecological tumor types and carries the worst prognosis. HSP90 is highly expressed in advanced ovarian carcinoma 9 and thus constitutes a potential therapeutic drug target. 10 In support, HSP90 inhibitors were found effective against ovarian cancer in preclinical models, 11-14 alone or in combination with conventional chemotherapy. 15,16 Carboplatin is the key component of all current first-line therapies for ovarian carcinoma. However, while initially often responding with regression, most tumors relapse and develop resistance within less than a year. 17,18 Like other platinum compounds, carboplatin acts by forming crosslinks within DNA. 17 Platinum compounds form intrastrand DNA lesions but also interstrand crosslinks (ICLs) by covalently linking opposite DNA strands. Such ICLs represent major obstacles to the DNA replication fork 19 and are therefore considered the principal toxic lesion of carboplatin's mode of action. The ICLs can only be removed by a sophisticated DNA repair systemthe Fanconi ...

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Section: Carbomentioning

confidence: 99%

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confidence: 99%

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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“…23 To investigate whether Roc-A acts as an intercalator, we compared the action of Roc-A to that of the DNA intercalation anticancer drug doxorubicin (trade name Adriamycin). 24 When DNA is damaged, DSBs trigger recruitment of ATM to the damage site which in turn phosphorylates histone H2AX (yielding gH2AX) leading to foci formation.…”

Section: Roc-a Does Not Induce Massive Dna Damage As Compared To Dnamentioning

confidence: 99%

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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“…Despite recent advances in our understanding of the molecular mechanisms of ICL repair, it remains to be determined how XPF‐ERCC1 processes the structures that arise during replication‐coupled ICL repair (Deans & West, 2011; Clauson et al , 2013). Here, we examined the activity of purified human XPF‐ERCC1 on DNA substrates that model native and ICL‐damaged replication forks.…”

Section: Introductionmentioning

confidence: 99%

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

et al. 2017

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During replication‐coupled DNA interstrand crosslink (ICL) repair, the XPF‐ERCC1 endonuclease is required for the incisions that release, or “unhook”, ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL. Here, we report that while purified XPF‐ERCC1 incises simple ICL‐containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity. Strikingly, the addition of the single‐stranded DNA (ssDNA)‐binding replication protein A (RPA) selectively restores XPF‐ERCC1 endonuclease activity on this structure. The 5′–3′ exonuclease SNM1A can load from the XPF‐ERCC1‐RPA‐induced incisions and digest past the crosslink to quantitatively complete the unhooking reaction. We postulate that these collaborative activities of XPF‐ERCC1, RPA and SNM1A might explain how ICL unhooking is achieved in vivo.

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DNA interstrand crosslink repair and cancer

Cited by 873 publications

References 159 publications

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

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