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Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A Yap, Maureen Hattersley, Mark J O'Connor, Huawei Chen, Stephen Fawell, Shiaw-Yih Lin, Guang Peng, Gordon B Mills
Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein)...
March 12, 2018: Cancer Cell
Jia Zhou, Jiaqi Li, Rodolfo B Serafim, Steven Ketchum, Catarina G Ferreira, Jessica C Liu, Kathryn A Coe, Brendan D Price, Timur Yusufzai
CHD1 is a conserved chromatin remodeling enzyme required for development and linked to prostate cancer in adults, yet its role in human cells is poorly understood. Here, we show that targeted disruption of the CHD1 gene in human cells leads to a defect in early double-strand break (DSB) repair via homologous recombination (HR), resulting in hypersensitivity to ionizing radiation as well as PARP and PTEN inhibition. CHD1 knockout cells show reduced H2AX phosphorylation (γH2AX) and foci formation as well as impairments in CtIP recruitment to the damaged sites...
February 26, 2018: Nucleic Acids Research
Cosimo Pinto, Roopesh Anand, Petr Cejka
DNA end resection initiates the largely accurate repair of DNA double-strand breaks (DSBs) by homologous recombination. Specifically, recombination requires the formation of 3' overhangs at DSB sites, which is carried out by nucleases that specifically degrade 5'-terminated DNA. In most cases, DNA end resection is a two-step process, comprising of initial short-range followed by more processive long-range resection. In this chapter, we describe selected assays that reconstitute both the short- and long-range pathways...
2018: Methods in Enzymology
Roopesh Anand, Cosimo Pinto, Petr Cejka
Accurate repair of DNA double-strand breaks (DSBs) is carried out by homologous recombination. In order to repair DNA breaks by the recombination pathway, the 5'-terminated DNA strand at DSB sites must be first nucleolytically processed to produce 3'-overhang. The process is termed DNA end resection and involves the interplay of several nuclease complexes. DNA end resection commits DSB repair to the recombination pathway including a process termed single-strand annealing, as resected DNA ends are generally nonligatable by the competing nonhomologous end-joining machinery...
2018: Methods in Enzymology
Jolein Mijnes, Jürgen Veeck, Nadine T Gaisa, Eduard Burghardt, Tim C de Ruijter, Sonja Gostek, Edgar Dahl, David Pfister, Sebastian C Schmid, Ruth Knüchel, Michael Rose
Background: Genome-wide studies identified pan-cancer genes and shared biological networks affected by epigenetic dysregulation among diverse tumor entities. Here, we systematically screened for hypermethylation of DNA damage repair (DDR) genes in a comprehensive candidate-approach and exemplarily identify and validate candidate DDR genes as targets of epigenetic inactivation unique to bladder cancer (BLCA), which may serve as non-invasive biomarkers. Methods: Genome-wide DNA methylation datasets (2755 CpG probes of n  = 7819 tumor and n  = 659 normal samples) of the TCGA network covering 32 tumor entities were analyzed in silico for 177 DDR genes...
2018: Clinical Epigenetics
Kazuhiro Nakajima, Yue Zhou, Akiko Tomita, Yoshihiro Hirade, Channabasavaiah B Gurumurthy, Shinichiro Nakada
CRISPR/Cas9, which generates DNA double-strand breaks (DSBs) at target loci, is a powerful tool for editing genomes when codelivered with a donor DNA template. However, DSBs, which are the most deleterious type of DNA damage, often result in unintended nucleotide insertions/deletions (indels) via mutagenic nonhomologous end joining. We developed a strategy for precise gene editing that does not generate DSBs. We show that a combination of single nicks in the target gene and donor plasmid (SNGD) using Cas9D10A nickase promotes efficient nucleotide substitution by gene editing...
December 22, 2017: Genome Research
Guo Chen, Jianxiang Chen, Yiting Qiao, Yaru Shi, Wei Liu, Qi Zeng, Hui Xie, Xiaorui Shi, Youwei Sun, Xu Liu, Tongyu Li, Liqian Zhou, Jianqin Wan, Tian Xie, Hangxiang Wang, Fu Wang
Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites...
December 13, 2017: Nucleic Acids Research
Ryo Sakasai, Mayu Isono, Mitsuo Wakasugi, Mitsumasa Hashimoto, Yumi Sunatani, Tadashi Matsui, Atsushi Shibata, Tsukasa Matsunaga, Kuniyoshi Iwabuchi
Accumulating evidence indicates that transcription is closely related to DNA damage formation and that the loss of RNA biogenesis factors causes genome instability. However, whether such factors are involved in DNA damage responses remains unclear. We focus here on the RNA helicase Aquarius (AQR), a known R-loop processing factor, and show that its depletion in human cells results in the accumulation of DNA damage during S phase, mediated by R-loop formation. We investigated the involvement of Aquarius in DNA damage responses and found that AQR knockdown decreased DNA damage-induced foci formation of Rad51 and replication protein A, suggesting that Aquarius contributes to homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs)...
October 23, 2017: Scientific Reports
Jiangman Lou, Hongxia Chen, Jinhua Han, Hanqing He, Michael S Y Huen, Xin-Hua Feng, Ting Liu, Jun Huang
DNA double-strand breaks (DSBs) are mainly repaired by either homologous recombination (HR) or non-homologous end-joining (NHEJ). Here, we identify AUNIP/C1orf135, a largely uncharacterized protein, as a key determinant of DSB repair pathway choice. AUNIP physically interacts with CtIP and is required for efficient CtIP accumulation at DSBs. AUNIP possesses intrinsic DNA-binding ability with a strong preference for DNA substrates that mimic structures generated at stalled replication forks. This ability to bind DNA is necessary for the recruitment of AUNIP and its binding partner CtIP to DSBs, which in turn drives CtIP-dependent DNA-end resection and HR repair...
October 17, 2017: Nature Communications
Delphine Lemaçon, Jessica Jackson, Annabel Quinet, Joshua R Brickner, Shan Li, Stephanie Yazinski, Zhongsheng You, Grzegorz Ira, Lee Zou, Nima Mosammaparast, Alessandro Vindigni
The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MRE11 nuclease, leading to chemotherapeutic sensitivity. Here we report that BRCA proteins prevent nucleolytic degradation by protecting replication forks that have undergone fork reversal upon drug treatment. The unprotected regressed arms of reversed forks are the entry point for MRE11 in BRCA-deficient cells...
October 16, 2017: Nature Communications
Alexis Fouquin, Josée Guirouilh-Barbat, Bernard Lopez, Janet Hall, Mounira Amor-Guéret, Vincent Pennaneach
Double strand breaks (DSBs) are one of the most toxic lesions to cells. DSB repair by the canonical non-homologous end-joining (C-EJ) pathway involves minor, if any, processing of the broken DNA-ends, whereas the initiation of DNA resection channels the broken-ends toward DNA repair pathways using various lengths of homology. Mechanisms that control the resection initiation are thus central to the regulation to the choice of DSB repair pathway. Therefore, understanding the mechanisms which regulate the initiation of DNA end-resection is of prime importance...
December 1, 2017: Nucleic Acids Research
Antonia Cagnetta, Debora Soncini, Stefania Orecchioni, Giovanna Talarico, Paola Minetto, Fabio Guolo, Veronica Retali, Nicoletta Colombo, Enrico Carminati, Marino Clavio, Maurizio Miglino, Micaela Bergamaschi, Aimable Nahimana, Michael Duchosal, Katia Todoerti, Antonino Neri, Mario Passalacqua, Santina Bruzzone, Alessio Nencioni, Francesco Bertolini, Marco Gobbi, Roberto M Lemoli, Michele Cea
Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia, and thus represents potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD+-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34+ blasts from Acute Myeloid Leukemia patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress...
October 12, 2017: Haematologica
James M Daley, Judit Jimenez-Sainz, Weibin Wang, Adam S Miller, Xiaoyu Xue, Kevin A Nguyen, Ryan B Jensen, Patrick Sung
DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway...
October 10, 2017: Cell Reports
Sharad C Paudyal, Shan Li, Hong Yan, Tony Hunter, Zhongsheng You
Nucleolytic resection of DNA double-strand breaks (DSBs) is essential for both checkpoint activation and homology-mediated repair; however, the precise mechanism of resection, especially the initiation step, remains incompletely understood. Resection of blocked ends with protein or chemical adducts is believed to be initiated by the MRN complex in conjunction with CtIP through internal cleavage of the 5' strand DNA. However, it is not clear whether resection of clean DSBs with free ends is also initiated by the same mechanism...
November 16, 2017: Nucleic Acids Research
Maria Jose Cabello-Lobato, Siyue Wang, Christine Katrin Schmidt
SAMHD1 (sterile α motif and histidine (H) aspartate (D) domain-containing protein 1) is known for its antiviral activity of hydrolysing deoxynucleotides required for virus replication. Daddacha et al. identify a hydrolase-independent, moonlighting function of SAMHD1 that facilitates homologous recombination of DNA double-strand breaks (DSBs) by promoting recruitment of C-terminal binding protein interacting protein (CTIP), a DNA-end resection factor, to damaged DNA. These findings could benefit anticancer treatment...
September 29, 2017: Trends in Genetics: TIG
Arancha Sanchez, Mariana C Gadaleta, Oliver Limbo, Paul Russell
The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe...
September 2017: PLoS Genetics
Waaqo Daddacha, Allyson E Koyen, Amanda J Bastien, PamelaSara E Head, Vishal R Dhere, Geraldine N Nabeta, Erin C Connolly, Erica Werner, Matthew Z Madden, Michele B Daly, Elizabeth V Minten, Donna R Whelan, Ashley J Schlafstein, Hui Zhang, Roopesh Anand, Christine Doronio, Allison E Withers, Caitlin Shepard, Ranjini K Sundaram, Xingming Deng, William S Dynan, Ya Wang, Ranjit S Bindra, Petr Cejka, Eli Rothenberg, Paul W Doetsch, Baek Kim, David S Yu
DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs...
August 22, 2017: Cell Reports
Isabel Soria-Bretones, Cristina Cepeda-García, Cintia Checa-Rodriguez, Vincent Heyer, Bernardo Reina-San-Martin, Evi Soutoglou, Pablo Huertas
DNA breaks are complex DNA lesions that can be repaired by two alternative mechanisms: non-homologous end-joining and homologous recombination. The decision between them depends on the activation of the DNA resection machinery, which blocks non-homologous end-joining and stimulates recombination. On the other hand, post-translational modifications play a critical role in DNA repair. We have found that the SUMO E3 ligase CBX4 controls resection through the key factor CtIP. Indeed, CBX4 depletion impairs CtIP constitutive sumoylation and DNA end processing...
July 24, 2017: Nature Communications
Sara N Andres, R Scott Williams
Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By modulating the nucleolytic 5'-3' resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities...
August 2017: DNA Repair
Oriane Bombarde, Florence Larminat, Dennis Gomez, Philippe Frit, Carine Racca, Bruno Gomes, Nicolas Guilbaud, Patrick Calsou
Poisons of Topoisomerase II (TOP2) kill cancer cells by preventing religation of intermediate DNA breaks during the enzymatic process and thus by accumulating enzyme-drug-DNA complexes called TOP2 cleavage-complex (TOP2cc). F14512 is a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived from etoposide and currently in clinical trials. It was shown in vitro that F14512 has acquired DNA binding properties and that the stability of TOP2cc was strongly increased. Paradoxically, at equitoxic concentrations in cells, F14512 induced less DNA breaks than etoposide...
June 13, 2017: Molecular Cancer Therapeutics
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