DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

Malik, Mobeen; Nitiss, John L.

doi:10.1128/ec.3.1.82-90.2004

Cited by 48 publications

(36 citation statements)

References 43 publications

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“…Saccharomyces cerevisiae cells defective in rad52 as well as strains with defects in other recombination repair genes, such as rad50, mre11, and rad54 mutants, are hypersensitive to topoisomerase II poisons (6,7). Similar results have been observed in fission yeast mutants that are defective in DNA repair by homologous recombination (8).…”

Section: Introductionsupporting

confidence: 61%

Roles of nonhomologous end-joining pathways in surviving topoisomerase II–mediated DNA damage

Malik

Nitiss

Enriquez-Rios

et al. 2006

Molecular Cancer Therapeutics

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Topoisomerase II is a target for clinically active anticancer drugs. Drugs targeting these enzymes act by preventing the religation of enzyme-DNA covalent complexes leading to protein-DNA adducts that include single-and doublestrand breaks. In mammalian cells, nonhomologous repair pathways are critical for repairing topoisomerase II -mediated DNA damage. Because topoisomerase IItargeting agents, such as etoposide, can also induce chromosomal translocations that can lead to secondary malignancies, understanding nonhomologous repair of topoisomerase II -mediated DNA damage may help to define strategies that limit this critical side effect on an important class of anticancer agents. Using Saccharomyces cerevisiae as a model eukaryote, we have determined the contribution of genes required for nonhomologous endjoining (NHEJ) for repairing DNA damage arising from treatment with topoisomerase II poisons, such as etoposide and 4 ¶-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA). To increase cellular sensitivity to topoisomerase II poisons, we overexpressed either wild-type or drughypersensitive alleles of yeast topoisomerase II. Using this approach, we found that yku70 (hdf1), yku80 (hdf2), and other genes required for NHEJ were important for cell survival following exposure to etoposide. The clearest increase in sensitivity was observed with cells overexpressing an etoposide-hypersensitive allele of TOP2 (Ser 740 Trp). Hypersensitivity was also seen in some end-joining defective mutants exposed to the intercalating agent mAMSA, although the increase in sensitivity was less pronounced. To confirm that the increase in sensitivity was not solely due to the elevated expression of TOP2 or due to specific effects of the drug-hypersensitive TOP2 alleles, we also found that deletion of genes required for NHEJ increased the sensitivity of rad52 deletions to both etoposide and mAMSA. Taken together, these results show a clear role for NHEJ in the repair of DNA damage induced by topoisomerase II -targeting agents and suggest that this pathway may participate in translocations generated by drugs, such as etoposide.

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Section: Introductionsupporting

confidence: 61%

Roles of nonhomologous end-joining pathways in surviving topoisomerase II–mediated DNA damage

Malik

Nitiss

Enriquez-Rios

et al. 2006

Molecular Cancer Therapeutics

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“…Cell Survival after CPT Treatment HR plays critical roles in suppressing genome instability and promoting cell survival after CPT exposure (Arnaudeau et al, 2001a;Malik and Nitiss, 2004;Sorensen et al, 2005). Thus, the conclusion reached above also suggests that Recql5 functions in a pathway that has a nonoverlapping role with HR with respect to cell survival after CPT treatment.…”

Section: Recql5 Functions Nonredundantly With Rad51 To Promotementioning

confidence: 79%

“…It is currently believed that the DSBs associated with such collapsed replication forks represent the main cytotoxic lesion induced by CPT (Ryan et al, 1991;Shao et al, 1999;Furuta et al, 2003). Consistent with this current hypothesis, it has been shown that homologous recombination repair (HRR) and the signal transduction cascade that is involved in this repair process both play critical roles in suppressing genome instability and promoting cell survival after CPT exposure (Arnaudeau et al, 2001a;Malik and Nitiss, 2004;Sorensen et al, 2005). Therefore, CPT has been widely used to interrogate the mechanisms involved in We recently reported that Recql5-deficient mouse cells were prone to gamma H2AX focus formation and gross chromosomal rearrangements (GCRs) after CPT treatment (Hu et al, 2007).…”

mentioning

confidence: 88%

“…A Significant Fraction of Recql5-deficient Cells Lost the Ability to Incorporate BrdU after CPT Treatment It has been reported previously that the cytotoxic effect of CPT is dependent on the collapse of replication forks (Hsiang et al, 1985;Holm et al, 1989;Ryan et al, 1991) and that HR plays a critical role in promoting cell survival after CPT exposure (Arnaudeau et al, 2001a;Malik and Nitiss, 2004;Sorensen et al, 2005). Therefore, a defect in either preventing forks from collapsing or HR-mediated repair could account for the CPT hypersensitivity observed in Recql5-deficient cells.…”

Section: Molecular Biology Of the Cell 116mentioning

confidence: 99%

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Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

Zhou

et al. 2009

MBoC

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Disruption of replication can lead to loss of genome integrity and increase of cancer susceptibility in mammals. Thus, a replication impediment constitutes a formidable challenge to these organisms. Recent studies indicate that homologous recombination (HR) plays an important role in suppressing genome instability and promoting cell survival after exposure to various replication inhibitors, including a topoisomerase I inhibitor, camptothecin (CPT). Here, we report that the deletion of RecQ helicase Recql5 in mouse ES cells and embryonic fibroblast (MEF) cells resulted in a significant increase in CPT sensitivity and a profound reduction in DNA replication after the treatment with CPT, but not other DNAdamaging agents. This CPT-induced cell death is replication dependent and occurs primarily after the cells had exited the first cell cycle after CPT treatment. Furthermore, we show that Recql5 functions nonredundantly with Rad51, a key factor for HR to protect mouse ES cells from CPT-induced cytotoxicity. These new findings strongly suggest that Recql5 plays an important role in maintaining active DNA replication to prevent the collapse of replication forks and the accumulation of DSBs in order to preserve genome integrity and to prevent cell death after replication stress as a result of topoisomerase I poisoning. INTRODUCTIONMammalian RecQ helicases share a high degree of homology with the RecQ helicase of Escherichia coli (Nakayama, 2002). These helicases have important roles in maintaining the integrity of the genomes and promoting cell survival in response to various types of genotoxic stress (Hickson, 2003). In addition, some of them have also been implicated in DNA replication (Oakley et al., 2002;Cheok et al., 2005). The only RecQ helicase in E. coli, RecQ, plays an important role in the recovery of genomic replication after DNA damage Hanawalt, 1999, 2001). In both budding yeast and fission yeast, there exist also just a single RecQ helicase. In both species, the RecQ helicase is involved in a number of DNA transaction processes, including repair, recombination and chromosome segregation (Hickson, 2003). Interestingly, these enzymes do not appear to be essential for processive DNA synthesis. Rather, they are required to prevent genomic instability by coordinating replication and recombination events at stalled replication forks (Lambert et al., 2007). Unlike unicellular organisms which have a single RecQ helicase, mammals possess a family of helicases encoded by five different genes, i.e., human RECQL, BLM, WRN, RECQL4, and RECQL5 (Hickson, 2003). Each of these five genes encodes one or multiple polypeptides with distinctive C-and/or N-terminal domains, suggesting that they have related but nonoverlapping functions.In particular, mutations in three of the five RecQ homologues, RECQL4, WRN, and BLM give rise to three distinct genomic instability and cancer-prone genetic disorders: Rothmund-Thomson, Werner, and Bloom syndromes, respectively (Ellis et al., 1995;Yu et al., 1996;Kitao et al., 1999). However, th...

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“…For instance, TDP2 can act as a backup pathway in the absence of TDP1 (29), and overexpression of TDP2 is sufficient to complement the hypersensitivity of TDP1-deficient budding yeast to camptothecin (CPT) (30). Mre11 has also been shown to cleave 3′-phosphotyrosyl-DNA bonds (31) and repair Top1cc in parallel with TDP1 (32)(33)(34). These results provide strong evidence that gkt encodes TDP1 in Drosophila.…”

Section: Resultsmentioning

confidence: 99%

Neuroprotection and repair of 3′-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1)

Guo¹,

Dexheimer

Pommier

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tyrosyl-DNA phosphodiesterase (TDP1) is a phylogenetically conserved enzyme critical for the removal of blocking lesions at the 3′ ends of DNA or RNA. This study analyzes the Drosophila TDP1 gene ortholog glaikit (gkt) and its possible role(s) in the repair of endogenous DNA lesions and neuroprotection. To do so, we studied a homozygous PiggyBac insertion (c03958) that disrupts the 5′ UTR of gkt. Protein extracts of c03958 flies were defective in hydrolyzing 3′-DNA-tyrosyl residues, demonstrating that gkt is the Drosophila TDP1. Although the mutant is generally healthy and fertile, females exhibit reduced lifespan and diminished climbing ability. This phenotype was rescued by neuronal expression of TDP1. In addition, when c03958 larvae were exposed to bleomycin, an agent that produces oxidative DNA damage, or topoisomerase I-targeted drugs (camptothecin and a noncamptothecin indenoisoquinoline derivative, LMP-776), survivors displayed rough eye patches, which were rescued by neuronal expression of TDP1. Our study establishes that gkt is the Drosophila TDP1 gene, and that it is critical for neuroprotection, normal longevity, and repair of damaged DNA.aging | neuroscience | DNA repair | topoisomerase | fly

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DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

Cited by 48 publications

References 43 publications

Roles of nonhomologous end-joining pathways in surviving topoisomerase II–mediated DNA damage

Roles of nonhomologous end-joining pathways in surviving topoisomerase II–mediated DNA damage

Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

Neuroprotection and repair of 3′-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1)

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