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Author

Elisabetta Leo

Other affiliations: National Institutes of Health
Bio: Elisabetta Leo is an academic researcher from AstraZeneca. The author has contributed to research in topics: Olaparib & PARP1. The author has an hindex of 11, co-authored 21 publications receiving 2131 citations. Previous affiliations of Elisabetta Leo include National Institutes of Health.

Papers
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Journal ArticleDOI
TL;DR: This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors and discusses the common mechanism of action ofTopoisomerase poisons by interfacial inhibition and trapping of topisomerase cleavage complexes.

1,587 citations

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TL;DR: It is concluded that SLFN11 expression is causally associated with the activity ofDDAs in cancer cells, has a broad expression range in colon and ovarian adenocarcinomas, and may behave as a biomarker for prediction of response to DDAs in the clinical setting.
Abstract: DNA-damaging agents (DDAs) constitute the backbone of treatment for most human tumors. Here we used the National Cancer Institute Antitumor Cell Line Panel (the NCI-60) to identify predictors of cancer cell response to topoisomerase I (Top1) inhibitors, a widely used class of DDAs. We assessed the NCI-60 transcriptome using Affymetrix Human Exon 1.0 ST microarrays and correlated the in vitro activity of four Top1 inhibitors with gene expression in the 60 cell lines. A single gene, Schlafen-11 (SLFN11), showed an extremely significant positive correlation with the response not only to Top1 inhibitors, but also to Top2 inhibitors, alkylating agents, and DNA synthesis inhibitors. Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, we show that SLFN11 is causative in determining cell death and cell cycle arrest in response to DDAs in cancer cells from different tissues of origin. We next analyzed SLFN11 expression in ovarian and colorectal cancers and normal corresponding tissues from The Cancer Genome Atlas database and observed that SLFN11 has a wide expression range. We also observed that high SLFN11 expression independently predicts overall survival in a group of ovarian cancer patients treated with cisplatin-containing regimens. We conclude that SLFN11 expression is causally associated with the activity of DDAs in cancer cells, has a broad expression range in colon and ovarian adenocarcinomas, and may behave as a biomarker for prediction of response to DDAs in the clinical setting.

232 citations

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TL;DR: It is concluded that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.

158 citations

Journal ArticleDOI
TL;DR: It is found that pharmacologic concentrations of SAHA induce replication-mediated DNA damage with activation of histone gammaH2AX, establishing a critical link between robust chromatin acetylation and DNA replication in human cancer cells.
Abstract: Protein acetylation is a reversible process regulated by histone deacetylases (HDAC) that is often altered in human cancers. Suberoylanilide hydroxamic acid (SAHA) is the first HDAC inhibitor to be approved for clinical use as an anticancer agent. Given that histone acetylation is a key determinant of chromatin structure, we investigated how SAHA may affect DNA replication and integrity to gain deeper insights into the basis for its anticancer activity. Nuclear replication factories were visualized with confocal immunofluorescence microscopy and single-replicon analyses were conducted by genome-wide molecular combing after pulse labeling with two thymidine analogues. We found that pharmacologic concentrations of SAHA induce replication-mediated DNA damage with activation of histone gammaH2AX. Single DNA molecule analyses indicated slowdown in replication speed along with activation of dormant replication origins in response to SAHA. Similar results were obtained using siRNA-mediated depletion of HDAC3 expression, implicating this HDAC member as a likely target in the SAHA response. Activation of dormant origins was confirmed by molecular analyses of the beta-globin locus control region. Our findings demonstrate that SAHA produces profound alterations in DNA replication that cause DNA damage, establishing a critical link between robust chromatin acetylation and DNA replication in human cancer cells.

139 citations

Journal ArticleDOI
TL;DR: V vertebrate Rif1 contains a DNA‐binding domain that resembles the αCTD domain of bacterial RNA polymerase α; and this domain preferentially binds fork and Holliday junction (HJ) DNA in vitro and is required for R if1 to resist replication stress in vivo.
Abstract: BLM, the helicase defective in Bloom syndrome, is part of a multiprotein complex that protects genome stability. Here, we show that Rif1 is a novel component of the BLM complex and works with BLM to promote recovery of stalled replication forks. First, Rif1 physically interacts with the BLM complex through a conserved C-terminal domain, and the stability of Rif1 depends on the presence of the BLM complex. Second, Rif1 and BLM are recruited with similar kinetics to stalled replication forks, and the Rif1 recruitment is delayed in BLM-deficient cells. Third, genetic analyses in vertebrate DT40 cells suggest that BLM and Rif1 work in a common pathway to resist replication stress and promote recovery of stalled forks. Importantly, vertebrate Rif1 contains a DNA-binding domain that resembles the αCTD domain of bacterial RNA polymerase α; and this domain preferentially binds fork and Holliday junction (HJ) DNA in vitro and is required for Rif1 to resist replication stress in vivo. Our data suggest that Rif1 provides a new DNA-binding interface for the BLM complex to restart stalled replication forks.

103 citations


Cited by
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Journal ArticleDOI
19 Jan 2012-Nature
TL;DR: A better understanding of the cellular response to DNA damage will not only inform the knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.
Abstract: Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall the cell cycle before the damaged DNA is passed on to daughter cells. Although these processes drive genomic instability and ultimately the disease process, they also provide therapeutic opportunities. A better understanding of the cellular response to DNA damage will not only inform our knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.

1,425 citations

Journal ArticleDOI
TL;DR: The development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic are highlighted.
Abstract: Histone deacetylases (HDACs) are a class of epigenetic enzymes that remove acetyl groups from lysine residues on histones and other proteins. In this Review, the authors highlight the role of HDACs in cancer, neurological diseases and immune disorders, and discuss the development of small-molecule inhibitors. Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators — histone deacetylases (HDACs) — and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.

1,261 citations

Journal ArticleDOI
Mark J. O'Connor1
TL;DR: The recent approval of olaparib (Lynparza) represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles' heel.

964 citations

Journal ArticleDOI
TL;DR: A model is emerging in which 53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with breast cancer 1 (BRCA1).
Abstract: DNA double-strand break (DSB) signalling and repair is crucial to preserve genomic integrity and maintain cellular homeostasis. p53-binding protein 1 (53BP1) is an important regulator of the cellular response to DSBs that promotes the end-joining of distal DNA ends, which is induced during V(D)J and class switch recombination as well as during the fusion of deprotected telomeres. New insights have been gained into the mechanisms underlying the recruitment of 53BP1 to damaged chromatin and how 53BP1 promotes non-homologous end-joining-mediated DSB repair while preventing homologous recombination. From these studies, a model is emerging in which 53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with breast cancer 1 (BRCA1).

895 citations