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Tomas Aparicio, Jean Gautier
DNA termini at double-strand breaks are often chemically heterogeneous and require processing before initiation of repair. In a recent report, we demonstrated that CtIP and the MRE11-RAD50-NBS1 (MRN) nuclease complex cooperate with BRCA1 to specifically repair topoisomerase II-DNA adducted breaks. In contrast, BRCA1 is dispensable for repair of restriction endonuclease-generated double-strand breaks.
July 2016: Molecular & Cellular Oncology
Pauline Chanut, Sébastien Britton, Julia Coates, Stephen P Jackson, Patrick Calsou
Repair of single-ended DNA double-strand breaks (seDSBs) by homologous recombination (HR) requires the generation of a 3' single-strand DNA overhang by exonuclease activities in a process called DNA resection. However, it is anticipated that the highly abundant DNA end-binding protein Ku sequesters seDSBs and shields them from exonuclease activities. Despite pioneering works in yeast, it is unclear how mammalian cells counteract Ku at seDSBs to allow HR to proceed. Here we show that in human cells, ATM-dependent phosphorylation of CtIP and the epistatic and coordinated actions of MRE11 and CtIP nuclease activities are required to limit the stable loading of Ku on seDSBs...
September 19, 2016: Nature Communications
Vijayalakshmi Kari, Wael Yassin Mansour, Sanjay Kumar Raul, Simon J Baumgart, Andreas Mund, Marian Grade, Hüseyin Sirma, Ronald Simon, Hans Will, Matthias Dobbelstein, Ekkehard Dikomey, Steven A Johnsen
The CHD1 gene, encoding the chromo-domain helicase DNA-binding protein-1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double-strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of CtIP to chromatin and subsequent end resection during DNA DSB repair. Our data support a role for CHD1 in opening the chromatin around the DSB to facilitate the recruitment of homologous recombination (HR) proteins. Consequently, depletion of CHD1 specifically affects HR-mediated DNA repair but not non-homologous end joining...
September 5, 2016: EMBO Reports
Lorenza P Ferretti, Sarah-Felicitas Himmels, Anika Trenner, Christina Walker, Christine von Aesch, Aline Eggenschwiler, Olga Murina, Radoslav I Enchev, Matthias Peter, Raimundo Freire, Antonio Porro, Alessandro A Sartori
Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein-protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway...
2016: Nature Communications
Yasuko Kamisugi, John W Whitaker, Andrew C Cuming
The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting...
2016: PloS One
Ana López-Saavedra, Daniel Gómez-Cabello, María Salud Domínguez-Sánchez, Fernando Mejías-Navarro, María Jesús Fernández-Ávila, Christoffel Dinant, María Isabel Martínez-Macías, Jiri Bartek, Pablo Huertas
There are two major and alternative pathways to repair DNA double-strand breaks: non-homologous end-joining and homologous recombination. Here we identify and characterize novel factors involved in choosing between these pathways; in this study we took advantage of the SeeSaw Reporter, in which the repair of double-strand breaks by homology-independent or -dependent mechanisms is distinguished by the accumulation of green or red fluorescence, respectively. Using a genome-wide human esiRNA (endoribonuclease-prepared siRNA) library, we isolate genes that control the recombination/end-joining ratio...
2016: Nature Communications
Ali Bakr, Sabrina Köcher, Jennifer Volquardsen, Cordula Petersen, Kerstin Borgmann, Ekkehard Dikomey, Kai Rothkamm, Wael Y Mansour
End processing at DNA double strand breaks (DSB) is a decisive step in repair pathway selection. Here, we investigated the role of 53BP1/RIF1 in limiting BRCA1/CtIP-mediated end resection to control DSB repair pathway choice. ATM orchestrates this process through 53BP1 phosphorylation to promote RIF1 recruitment. As cells enter S/G2-phase, end resection is activated, which displaces pATM from DSB sites and diminishes 53BP1 phosphorylation and RIF1 recruitment. Consistently, the kinetics of ATM and 53BP1 phosphorylation in S/G2-phase concur...
August 2, 2016: Oncotarget
Wenwen Wu, Yukiko Togashi, Yoshikazu Johmura, Yasuo Miyoshi, Sachihiko Nobuoka, Makoto Nakanishi, Tomohiko Ohta
The breast and ovarian cancer predisposition protein BRCA1 forms three mutually exclusive complexes with FANCJ (also called BACH1 or BRIP1), CtIP and Abraxas/RAP80 through its BRCT domains, while its RING domain binds to BARD1. We recently found that the interaction of HP1 with BARD1 is required for the accumulation of BRCA1 and CtIP at sites of DNA double-strand breaks (DSBs). Here, we investigated the importance of the HP1 and BARD1-HP1 interaction in the localization of FANCJ together with the other BRCA1-BRCT-binding proteins to clarify the separate role of the HP1-mediated pathway from the RNF8/RNF168-induced ubiquitin-mediated pathway for BRCA1 function...
July 11, 2016: Cancer Science
Kristi L Jensen, Paul Russell
Homologous recombination (HR) repair of programmed meiotic double-strand breaks (DSBs) requires endonucleolytic clipping of Rec12(Spo11)-oligonucleotides from 5' DNA ends followed by resection to generate invasive 3' single-stranded DNA tails. The Mre11-Rad50-Nbs1 (MRN) endonuclease and Ctp1 (CtIP and Sae2 ortholog) are required for both activities in fission yeast but whether they are genetically separable is controversial. Here, we investigate the mitotic DSB repair properties of Ctp1 C-terminal domain (ctp1-CD) mutants that were reported to be specifically clipping deficient...
September 30, 2016: Nucleic Acids Research
Huiming Lu, Raghavendra A Shamanna, Guido Keijzers, Roopesh Anand, Lene Juel Rasmussen, Petr Cejka, Deborah L Croteau, Vilhelm A Bohr
The RecQ helicase RECQL4, mutated in Rothmund-Thomson syndrome, regulates genome stability, aging, and cancer. Here, we identify a crucial role for RECQL4 in DNA end resection, which is the initial and an essential step of homologous recombination (HR)-dependent DNA double-strand break repair (DSBR). Depletion of RECQL4 severely reduces HR-mediated repair and 5' end resection in vivo. RECQL4 physically interacts with MRE11-RAD50-NBS1 (MRN), which senses DSBs and initiates DNA end resection with CtIP. The MRE11 exonuclease regulates the retention of RECQL4 at laser-induced DSBs...
June 28, 2016: Cell Reports
Takayo Fukuda, Tomoko Tsuruga, Takako Kuroda, Jun Takeuchi, Wenwen Wu, Tomohiko Ohta
Chromatin compaction represents a barrier for the repair of DNA double-strand breaks (DSBs). However, heterochromatin components are also required for DSB repair by homologous recombination. The BARD1/HP1 interaction, required for the retention of BRCA1, CTIP, and RAD51 at DSB sites, may play a critical role in the crosstalk between chromatin compaction and DSB repair.
March 2016: Molecular & Cellular Oncology
Lorenzo Lafranchi, Alessandro A Sartori
DNA double-strand breaks (DSBs) are highly deleterious lesions and their misrepair can promote genomic instability, a hallmark of cancer. DNA-end resection is a cell cycle-regulated mechanism that is required for the faithful repair of DSBs. We recently discovered that the anaphase-promoting complex/cyclosome-Cdh1 (APC/C(Cdh1)) ubiquitin ligase is responsible for the timely degradation of CtBP-interacting protein (CtIP), a key DNA-end resection factor, providing a new layer of regulation of DSB repair in human cells...
October 2015: Molecular & Cellular Oncology
Vijay Menon, Lawrence F Povirk
Nonhomologous end joining (NHEJ) is an error-prone DNA double-strand break repair pathway that is active throughout the cell cycle. A substantial fraction of NHEJ repair events show deletions and, less often, insertions in the repair joints, suggesting an end-processing step comprising the removal of mismatched or damaged nucleotides by nucleases and other phosphodiesterases, as well as subsequent strand extension by polymerases. A wide range of nucleases, including Artemis, Metnase, APLF, Mre11, CtIP, APE1, APE2 and WRN, are biochemically competent to carry out such double-strand break end processing, and have been implicated in NHEJ by at least circumstantial evidence...
July 2016: DNA Repair
Nobuo Horikoshi, Raj K Pandita, Kalpana Mujoo, Shashank Hambarde, Dharmendra Sharma, Abid R Mattoo, Sharmistha Chakraborty, Vijaya Charaka, Clayton R Hunt, Tej K Pandita
β2-Spectrin (β2SP/SPTBN1, gene SPTBN1) is a key TGF-β/SMAD3/4 adaptor and transcriptional cofactor that regulates TGF-β signaling and can contribute to liver cancer development. Here we report that cells deficient in β2-Spectrin (β2SP) are moderately sensitive to ionizing radiation (IR) and extremely sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with IR or ICL agents (formaldehyde, cisplatin, camptothecin, mitomycin), β2SP deficient cells displayed a higher frequency of cells with delayed γ-H2AX removal and a higher frequency of residual chromosome aberrations...
June 7, 2016: Oncotarget
Ting Liu, Jun Huang
DNA double-strand breaks (DSBs), which arise following exposure to a number of endogenous and exogenous agents, can be repaired by either the homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways in eukaryotic cells. A vital step in HR repair is DNA end resection, which generates a long 3' single-stranded DNA (ssDNA) tail that can invade the homologous DNA strand. The generation of 3' ssDNA is not only essential for HR repair, but also promotes activation of the ataxia telangiectasia and Rad3-related protein (ATR)...
June 2016: Genomics, Proteomics & Bioinformatics
Yao Zhang, Jinzhi Lai, Zhanwen Du, Jinnan Gao, Shuming Yang, Shashank Gorityala, Xiahui Xiong, Ou Deng, Zhefu Ma, Chunhong Yan, Gonzalo Susana, Yan Xu, Junran Zhang
Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes...
June 7, 2016: Oncotarget
Durga Udayakumar, Raj K Pandita, Nobuo Horikoshi, Yan Liu, Qingsong Liu, Kwok-Kin Wong, Clayton R Hunt, Nathanael S Gray, John D Minna, Tej K Pandita, Kenneth D Westover
Several classes of inhibitors of the mammalian target of rapamycin (mTOR) have been developed based on its central role in sensing growth factor and nutrient levels to regulate cellular metabolism. However, its ATP-binding site closely resembles other phosphatidylinositol 3-kinase-related kinase (PIKK) family members, resulting in reactivity with these targets that may also be therapeutically useful. The ATP-competitive mTOR inhibitor, Torin2, shows biochemical activity against the DNA repair-associated proteins ATM, ATR and DNA-PK, which raises the possibility that Torin2 and related compounds might radiosensitize cancerous tumors...
May 2016: Radiation Research
Sara Ahrabi, Sovan Sarkar, Sophia X Pfister, Giacomo Pirovano, Geoff S Higgins, Andrew C G Porter, Timothy C Humphrey
DNA double-strand breaks (DSBs) are toxic lesions, which if improperly repaired can result in cell death or genomic instability. DSB repair is usually facilitated by the classical non-homologous end joining (C-NHEJ), or homologous recombination (HR) pathways. However, a mutagenic alternative NHEJ pathway, microhomology-mediated end joining (MMEJ), can also be deployed. While MMEJ is suppressed by C-NHEJ, the relationship between HR and MMEJ is less clear. Here, we describe a role for HR genes in suppressing MMEJ in human cells...
July 8, 2016: Nucleic Acids Research
Lorraine S Symington
The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is initiated by nucleolytic degradation of the 5'-terminated strands in a process termed end resection. End resection generates 3'-single-stranded DNA tails, substrates for Rad51 to catalyze homologous pairing and DNA strand exchange, and for activation of the DNA damage checkpoint. The commonly accepted view is that end resection occurs by a two-step mechanism. In the first step, Sae2/CtIP activates the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex to endonucleolytically cleave the 5'-terminated DNA strands close to break ends, and in the second step Exo1 and/or Dna2 nucleases extend the resected tracts to produce long 3'-ssDNA-tailed intermediates...
May 2016: Critical Reviews in Biochemistry and Molecular Biology
David O Onyango, Sean M Howard, Kashfia Neherin, Diana A Yanez, Jeremy M Stark
We examined the influence of the tetratricopeptide repeat factor XAB2 on chromosomal break repair, and found that XAB2 promotes end resection that generates the 3' ssDNA intermediate for homologous recombination (HR). Namely, XAB2 is important for chromosomal double-strand break (DSB) repair via two pathways of HR that require end resection as an intermediate step, end resection of camptothecin (Cpt)-induced DNA damage, and RAD51 recruitment to ionizing radiation induced foci (IRIF), which requires end resection...
July 8, 2016: Nucleic Acids Research
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