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Results: 1 to 10 of 15

Publication Record


HMCES Maintains Genome Integrity by Shielding Abasic Sites in Single-Strand DNA.
Mohni KN, Wessel SR, Zhao R, Wojciechowski AC, Luzwick JW, Layden H, Eichman BF, Thompson PS, Mehta KPM, Cortez D
(2019) Cell 176: 144-153.e13
MeSH Terms: 5-Methylcytosine, Apurinic Acid, DNA, DNA Damage, DNA Repair, DNA Replication, DNA, Single-Stranded, DNA-Binding Proteins, Endonucleases, Escherichia coli, Polynucleotides, Proliferating Cell Nuclear Antigen
Show Abstract · Added August 26, 2019
Abasic sites are one of the most common DNA lesions. All known abasic site repair mechanisms operate only when the damage is in double-stranded DNA. Here, we report the discovery of 5-hydroxymethylcytosine (5hmC) binding, ESC-specific (HMCES) as a sensor of abasic sites in single-stranded DNA. HMCES acts at replication forks, binds PCNA and single-stranded DNA, and generates a DNA-protein crosslink to shield abasic sites from error-prone processing. This unusual HMCES DNA-protein crosslink intermediate is resolved by proteasome-mediated degradation. Acting as a suicide enzyme, HMCES prevents translesion DNA synthesis and the action of endonucleases that would otherwise generate mutations and double-strand breaks. HMCES is evolutionarily conserved in all domains of life, and its biochemical properties are shared with its E. coli ortholog. Thus, HMCES is an ancient DNA lesion recognition protein that preserves genome integrity by promoting error-free repair of abasic sites in single-stranded DNA.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
1 Members
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12 MeSH Terms
Comparative analysis of chimeric ZFP-, TALE- and Cas9-piggyBac transposases for integration into a single locus in human cells.
Luo W, Galvan DL, Woodard LE, Dorset D, Levy S, Wilson MH
(2017) Nucleic Acids Res 45: 8411-8422
MeSH Terms: Bacterial Proteins, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Cell Line, Tumor, DNA Transposable Elements, Endonucleases, Gene Knockout Techniques, Gene Targeting, Gene Transfer Techniques, Humans, Hypoxanthine Phosphoribosyltransferase, Mutagenesis, Insertional, Recombinant Fusion Proteins, Reproducibility of Results, Transcription Activator-Like Effector Nucleases, Transcription Activator-Like Effectors, Transposases, Zinc Fingers
Show Abstract · Added September 11, 2017
Integrating DNA delivery systems hold promise for many applications including treatment of diseases; however, targeted integration is needed for improved safety. The piggyBac (PB) transposon system is a highly active non-viral gene delivery system capable of integrating defined DNA segments into host chromosomes without requiring homologous recombination. We systematically compared four different engineered zinc finger proteins (ZFP), four transcription activator-like effector proteins (TALE), CRISPR associated protein 9 (SpCas9) and the catalytically inactive dSpCas9 protein fused to the amino-terminus of the transposase enzyme designed to target the hypoxanthine phosphoribosyltransferase (HPRT) gene located on human chromosome X. Chimeric transposases were evaluated for expression, transposition activity, chromatin immunoprecipitation at the target loci, and targeted knockout of the HPRT gene in human cells. One ZFP-PB and one TALE-PB chimera demonstrated notable HPRT gene targeting. In contrast, Cas9/dCas9-PB chimeras did not result in gene targeting. Instead, the HPRT locus appeared to be protected from transposon integration. Supplied separately, PB permitted highly efficient isolation of Cas9-mediated knockout of HPRT, with zero transposon integrations in HPRT by deep sequencing. In summary, these tools may allow isolation of 'targeted-only' cells, be utilized to protect a genomic locus from transposon integration, and enrich for Cas9-mutated cells.
Published by Oxford University Press on behalf of Nucleic Acids Research 2017.
0 Communities
2 Members
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18 MeSH Terms
Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing.
Tsai SQ, Wyvekens N, Khayter C, Foden JA, Thapar V, Reyon D, Goodwin MJ, Aryee MJ, Joung JK
(2014) Nat Biotechnol 32: 569-76
MeSH Terms: Bacterial Proteins, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Deoxyribonucleases, Type II Site-Specific, Endonucleases, Gene Editing, Humans, Protein Multimerization, RNA, Guide, Recombinant Fusion Proteins
Show Abstract · Added January 26, 2015
Monomeric CRISPR-Cas9 nucleases are widely used for targeted genome editing but can induce unwanted off-target mutations with high frequencies. Here we describe dimeric RNA-guided FokI nucleases (RFNs) that can recognize extended sequences and edit endogenous genes with high efficiencies in human cells. RFN cleavage activity depends strictly on the binding of two guide RNAs (gRNAs) to DNA with a defined spacing and orientation substantially reducing the likelihood that a suitable target site will occur more than once in the genome and therefore improving specificities relative to wild-type Cas9 monomers. RFNs guided by a single gRNA generally induce lower levels of unwanted mutations than matched monomeric Cas9 nickases. In addition, we describe a simple method for expressing multiple gRNAs bearing any 5' end nucleotide, which gives dimeric RFNs a broad targeting range. RFNs combine the ease of RNA-based targeting with the specificity enhancement inherent to dimerization and are likely to be useful in applications that require highly precise genome editing.
0 Communities
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3 Resources
10 MeSH Terms
ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency.
Mohni KN, Kavanaugh GM, Cortez D
(2014) Cancer Res 74: 2835-45
MeSH Terms: Ataxia Telangiectasia Mutated Proteins, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, DNA Damage, DNA-Binding Proteins, Endonucleases, HCT116 Cells, HEK293 Cells, Humans, Lung Neoplasms, Micronucleus Tests, Molecular Targeted Therapy, RNA, Small Interfering, Transfection, Triple Negative Breast Neoplasms
Show Abstract · Added May 19, 2014
The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions, with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase cyclin E. Here, we report a systematic screen to identify synthetic lethal interactions with ATR pathway-targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure-specific endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1-deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells were arrested in S-phase and failed to complete cell-cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non-small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR pathway-targeted drugs. Overall, we concluded that ATR pathway-targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity.
©2014 American Association for Cancer Research.
0 Communities
1 Members
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15 MeSH Terms
Identification and characterization of SMARCAL1 protein complexes.
Bétous R, Glick GG, Zhao R, Cortez D
(2013) PLoS One 8: e63149
MeSH Terms: Cell Line, Tumor, DNA, DNA Breaks, Double-Stranded, DNA Helicases, DNA Repair, DNA Replication, DNA-Binding Proteins, Endonucleases, Exodeoxyribonucleases, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Immunoprecipitation, Mass Spectrometry, Nucleic Acid Conformation, Protein Binding, Proteomics, RecQ Helicases, Replication Protein A, S Phase, Werner Syndrome Helicase
Show Abstract · Added March 5, 2014
SMARCAL1 is an ATPase in the SNF2 family that functions at damaged replication forks to promote their stability and restart. It acts by translocating on DNA to catalyze DNA strand annealing, branch migration, and fork regression. Many SNF2 enzymes work as motor subunits of large protein complexes. To determine if SMARCAL1 is also a member of a protein complex and to further understand how it functions in the replication stress response, we used a proteomics approach to identify interacting proteins. In addition to the previously characterized interaction with replication protein A (RPA), we found that SMARCAL1 forms complexes with several additional proteins including DNA-PKcs and the WRN helicase. SMARCAL1 and WRN co-localize at stalled replication forks independently of one another. The SMARCAL1 interaction with WRN is indirect and is mediated by RPA acting as a scaffold. SMARCAL1 and WRN act independently to prevent MUS81 cleavage of the stalled fork. Biochemical experiments indicate that both catalyze fork regression with SMARCAL1 acting more efficiently and independently of WRN. These data suggest that RPA brings a complex of SMARCAL1 and WRN to stalled forks, but that they may act in different pathways to promote fork repair and restart.
0 Communities
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22 MeSH Terms
SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication.
Bétous R, Mason AC, Rambo RP, Bansbach CE, Badu-Nkansah A, Sirbu BM, Eichman BF, Cortez D
(2012) Genes Dev 26: 151-62
MeSH Terms: Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Helicases, DNA Replication, DNA, Cruciform, DNA, Single-Stranded, DNA-Binding Proteins, Endonucleases, Genomic Instability, HEK293 Cells, Humans, Protein Binding, Protein Structure, Tertiary, S Phase
Show Abstract · Added March 5, 2014
SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1) maintains genome integrity during DNA replication. Here we investigated its mechanism of action. We found that SMARCAL1 travels with elongating replication forks, and its absence leads to MUS81-dependent double-strand break formation. Binding to specific nucleic acid substrates activates SMARCAL1 activity in a reaction that requires its HARP2 (Hep-A-related protein 2) domain. Homology modeling indicates that the HARP domain is similar in structure to the DNA-binding domain of the PUR proteins. Limited proteolysis, small-angle X-ray scattering, and functional assays indicate that the core enzymatic unit consists of the HARP2 and ATPase domains that fold into a stable structure. Surprisingly, SMARCAL1 is capable of binding three-way and four-way Holliday junctions and model replication forks that lack a designed ssDNA region. Furthermore, SMARCAL1 remodels these DNA substrates by promoting branch migration and fork regression. SMARCAL1 mutations that cause Schimke immunoosseous dysplasia or that inactivate the HARP2 domain abrogate these activities. These results suggest that SMARCAL1 continuously surveys replication forks for damage. If damage is present, it remodels the fork to promote repair and restart. Failures in the process lead to activation of an alternative repair mechanism that depends on MUS81-catalyzed cleavage of the damaged fork.
1 Communities
2 Members
0 Resources
14 MeSH Terms
Genetic engineering of human pluripotent cells using TALE nucleases.
Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, Cost GJ, Zhang L, Santiago Y, Miller JC, Zeitler B, Cherone JM, Meng X, Hinkley SJ, Rebar EJ, Gregory PD, Urnov FD, Jaenisch R
(2011) Nat Biotechnol 29: 731-4
MeSH Terms: Base Sequence, Embryonic Stem Cells, Endonucleases, Gene Targeting, Genetic Engineering, Homeodomain Proteins, Humans, Induced Pluripotent Stem Cells, Molecular Sequence Data, Myosin-Light-Chain Phosphatase, Octamer Transcription Factor-3, Transcription Factors, Zinc Fingers
Show Abstract · Added June 6, 2012
Targeted genetic engineering of human pluripotent cells is a prerequisite for exploiting their full potential. Such genetic manipulations can be achieved using site-specific nucleases. Here we engineered transcription activator-like effector nucleases (TALENs) for five distinct genomic loci. At all loci tested we obtained human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) clones carrying transgenic cassettes solely at the TALEN-specified location. Our data suggest that TALENs employing the specific architectures described here mediate site-specific genome modification in human pluripotent cells with similar efficiency and precision as do zinc-finger nucleases (ZFNs).
1 Communities
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13 MeSH Terms
Nucleotide excision repair genes and risk of lung cancer among San Francisco Bay Area Latinos and African Americans.
Chang JS, Wrensch MR, Hansen HM, Sison JD, Aldrich MC, Quesenberry CP, Seldin MF, Kelsey KT, Kittles RA, Silva G, Wiencke JK
(2008) Int J Cancer 123: 2095-104
MeSH Terms: African Americans, Aged, DNA Ligase ATP, DNA Ligases, DNA Repair, DNA-Binding Proteins, Endonucleases, Female, Haplotypes, Hispanic Americans, Humans, Lung Neoplasms, Male, Middle Aged, Nuclear Proteins, Polymorphism, Single Nucleotide, Principal Component Analysis, Risk, Smoking, Transcription Factors, Xeroderma Pigmentosum Group D Protein
Show Abstract · Added February 26, 2014
Few studies on the association between nucleotide excision repair (NER) variants and lung cancer risk have included Latinos and African Americans. We examine variants in 6 NER genes (ERCC2, ERCC4, ERCC5, LIG1, RAD23B and XPC) in association with primary lung cancer risk among 113 Latino and 255 African American subjects newly diagnosed with primary lung cancer from 1998 to 2003 in the San Francisco Bay Area and 579 healthy controls (299 Latinos and 280 African Americans). Individual single nucleotide polymorphism and haplotype analyses, multifactor dimensionality reduction (MDR) and principal components analysis (PCA) were performed to assess the association between 6 genes in the NER pathway and lung cancer risk. Among Latinos, ERCC2 haplotype CGA (rs238406, rs11878644, rs6966) was associated with reduced lung cancer risk [odds ratio (OR) of 0.65 and 95% confidence interval (CI): 0.44-0.97], especially among nonsmokers (OR = 0.29; 95% CI: 0.12-0.67). From MDR analysis, in Latinos, smoking and 3 SNPs (ERCC2 rs171140, ERCC5 rs17655 and LIG1 rs20581) together had a prediction accuracy of 67.4% (p = 0.001) for lung cancer. Among African Americans, His/His genotype of ERCC5 His1104Asp (rs17655) was associated with increased lung cancer risk (OR = 1.78; 95% CI: 1.09-2.91), and LIG1 haplotype GGGAA (rs20581, rs156641, rs3730931, rs20579 and rs439132) was associated with reduced lung cancer risk (OR = 0.61; 95% CI: 0.42-0.88). Our study suggests different elements of the NER pathway may be important in the different ethnic groups resulting either from different linkage relationship, genetic backgrounds and/or exposure histories.
(c) 2008 Wiley-Liss, Inc.
0 Communities
1 Members
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21 MeSH Terms
Molecularly tailored adjuvant chemotherapy for resected non-small cell lung cancer: a time for excitement and equipoise.
Azzoli CG, Park BJ, Pao W, Zakowski M, Kris MG
(2008) J Thorac Oncol 3: 84-93
MeSH Terms: Antineoplastic Agents, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Chemotherapy, Adjuvant, Cisplatin, Clinical Trials as Topic, Cyclin-Dependent Kinase Inhibitor p27, DNA-Binding Proteins, Endonucleases, Follow-Up Studies, Genes, erbB-1, Humans, Intracellular Signaling Peptides and Proteins, Lung Neoplasms, Membrane Transport Proteins, Multidrug Resistance-Associated Proteins, Neoplasm Staging, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Randomized Controlled Trials as Topic, Survival Analysis, Time Factors, Treatment Outcome, Tubulin, ras Proteins
Show Abstract · Added March 24, 2014
In patients with previously-untreated, completely-resected pathologic stage II-III non-small cell lung cancer, 4 months of postoperative cisplatin-based chemotherapy reduces the risk of death by approximately 20%. To date, the only prospectively validated prognostic and predictive factor which can be used to guide clinical practice is pathologic stage. Higher stage patients have a worse prognosis, but derive more benefit from adjuvant chemotherapy. Numerous molecular markers are being developed with the potential to help decide which patients to treat with adjuvant chemotherapy, and which drugs to use. This paper will review the molecular markers which are having immediate impact on treatment decisions in routine practice, and which merit further study in the next generation of adjuvant chemotherapy trials.
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25 MeSH Terms
The Nse5-Nse6 dimer mediates DNA repair roles of the Smc5-Smc6 complex.
Pebernard S, Wohlschlegel J, McDonald WH, Yates JR, Boddy MN
(2006) Mol Cell Biol 26: 1617-30
MeSH Terms: Carrier Proteins, Cell Cycle Proteins, Chromosomal Proteins, Non-Histone, DNA Helicases, DNA Repair, DNA Replication, DNA-Binding Proteins, Dimerization, Endonucleases, Escherichia coli Proteins, Genome, Fungal, Genomic Instability, Holliday Junction Resolvases, Multiprotein Complexes, Mutation, Nuclear Proteins, Recombinant Proteins, Recombination, Genetic, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Ultraviolet Rays
Show Abstract · Added March 20, 2014
Stabilization and processing of stalled replication forks is critical for cell survival and genomic integrity. We characterize a novel DNA repair heterodimer of Nse5 and Nse6, which are nonessential nuclear proteins critical for chromosome segregation in fission yeast. The Nse5/6 dimer facilitates DNA repair as part of the Smc5-Smc6 holocomplex (Smc5/6), the basic architecture of which we define. Nse5-Nse6 [corrected] (Nse5 and Nse6) [corrected] mutants display a high level of spontaneous DNA damage and mitotic catastrophe in the absence of the master checkpoint regulator Rad3 (hATR). Nse5/6 mutants are required for the response to genotoxic agents that block the progression of replication forks, acting in a pathway that allows the tolerance of irreparable UV lesions. Interestingly, the UV sensitivity of Nse5/6 [corrected] is suppressed by concomitant deletion of the homologous recombination repair factor, Rhp51 (Rad51). Further, the viability of Nse5/6 mutants depends on Mus81 and Rqh1, factors that resolve or prevent the formation of Holliday junctions. Consistently, the UV sensitivity of cells lacking Nse5/6 can be partially suppressed by overexpressing the bacterial resolvase RusA. We propose a role for Nse5/6 mutants in suppressing recombination that results in Holliday junction formation or in Holliday junction resolution.
0 Communities
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21 MeSH Terms