当前位置： SCI文献检索 > NATURE GENETICS期刊下所有文献 > Cas9 activates the p53 pathway and selects for p53-inactivating mutations.

Cas9 activates the p53 pathway and selects for p53-inactivating mutations.

Abstract：

:Cas9 is commonly introduced into cell lines to enable CRISPR-Cas9-mediated genome editing. Here, we studied the genetic and transcriptional consequences of Cas9 expression itself. Gene expression profiling of 165 pairs of human cancer cell lines and their Cas9-expressing derivatives revealed upregulation of the p53 pathway upon introduction of Cas9, specifically in wild-type TP53 (TP53-WT) cell lines. This was confirmed at the messenger RNA and protein levels. Moreover, elevated levels of DNA repair were observed in Cas9-expressing cell lines. Genetic characterization of 42 cell line pairs showed that introduction of Cas9 can lead to the emergence and expansion of p53-inactivating mutations. This was confirmed by competition experiments in isogenic TP53-WT and TP53-null (TP53-/-) cell lines. Lastly, Cas9 was less active in TP53-WT than in TP53-mutant cell lines, and Cas9-induced p53 pathway activation affected cellular sensitivity to both genetic and chemical perturbations. These findings may have broad implications for the proper use of CRISPR-Cas9-mediated genome editing.

journal_name

Nat Genet

journal_title

Nature genetics

authors

Enache OM,Rendo V,Abdusamad M,Lam D,Davison D,Pal S,Currimjee N,Hess J,Pantel S,Nag A,Thorner AR,Doench JG,Vazquez F,Beroukhim R,Golub TR,Ben-David U

doi

10.1038/s41588-020-0623-4

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

662-668

issue

7

eissn

1061-4036

issn

1546-1718

pii

10.1038/s41588-020-0623-4

journal_volume

52

pub_type

杂志文章

相关文献

NATURE GENETICS文献大全
  • Mutations in SECISBP2 result in abnormal thyroid hormone metabolism.

    abstract：:Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNA(Sec) die in utero, but the in vivo role of other components involved in selenoprotein synthesis is unknown, and Sec incorporation defects have not been described in humans. Deiodinases (...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng1654

    authors： Dumitrescu AM,Liao XH,Abdullah MS,Lado-Abeal J,Majed FA,Moeller LC,Boran G,Schomburg L,Weiss RE,Refetoff S

    更新日期：2005-11-01 00:00:00

  • A double-stranded RNA binding protein required for activation of repressed messages in mammalian germ cells.

    abstract：:Chromatin packaging in mammalian spermatozoa requires an ordered replacement of the somatic histones by two classes of spermatid-specific basic proteins, the transition proteins and the protamines. Temporal expression of transition proteins and protamines during spermatid differentiation is under translational control...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/9684

    authors： Zhong J,Peters AH,Lee K,Braun RE

    更新日期：1999-06-01 00:00:00

  • Genomic analysis of Andamanese provides insights into ancient human migration into Asia and adaptation.

    abstract：:To shed light on the peopling of South Asia and the origins of the morphological adaptations found there, we analyzed whole-genome sequences from 10 Andamanese individuals and compared them with sequences for 60 individuals from mainland Indian populations with different ethnic histories and with publicly available da...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.3621

    authors： Mondal M,Casals F,Xu T,Dall'Olio GM,Pybus M,Netea MG,Comas D,Laayouni H,Li Q,Majumder PP,Bertranpetit J

    更新日期：2016-09-01 00:00:00

  • Direct detection of novel expanded trinucleotide repeats in the human genome.

    abstract：:Expansion of trinucleotide repeats can give rise to genetic disease. We have developed a technique, repeat expansion detection (RED), that can identify potentially pathological repeat expansion without prior knowledge of chromosomal location. Human genomic DNA is used as a template for a two-step cycling process that ...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng0693-135

    authors： Schalling M,Hudson TJ,Buetow KH,Housman DE

    更新日期：1993-06-01 00:00:00

  • The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.

    abstract：:Characterization of the polycystic kidney disease 1 (PKD1) gene has been complicated by genomic rearrangements on chromosome 16. We have used an exon linking strategy, taking RNA from a cell line containing PKD1 but not the duplicate loci, to clone a cDNA contig of the entire transcript. The transcript consists of 14,...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng0695-151

    authors： Hughes J,Ward CJ,Peral B,Aspinwall R,Clark K,San Millán JL,Gamble V,Harris PC

    更新日期：1995-06-01 00:00:00

  • SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination.

    abstract：:The Escherichia coli gene recQ was identified as a RecF recombination pathway gene. The gene SGS1, encoding the only RecQ-like DNA helicase in Saccharomyces cerevisiae, was identified by mutations that suppress the top3 slow-growth phenotype. Relatively little is known about the function of Sgs1p because single mutati...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/83673

    authors： Myung K,Datta A,Chen C,Kolodner RD

    更新日期：2001-01-01 00:00:00

  • Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.

    abstract：:CASK is a multi-domain scaffolding protein that interacts with the transcription factor TBR1 and regulates expression of genes involved in cortical development such as RELN. Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK. All five affected individuals with CAS...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.194

    authors： Najm J,Horn D,Wimplinger I,Golden JA,Chizhikov VV,Sudi J,Christian SL,Ullmann R,Kuechler A,Haas CA,Flubacher A,Charnas LR,Uyanik G,Frank U,Klopocki E,Dobyns WB,Kutsche K

    更新日期：2008-09-01 00:00:00

  • Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene.

    abstract：:Refsum disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells in the CSF. All patients exhibit ac...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng1097-190

    authors： Jansen GA,Ofman R,Ferdinandusse S,Ijlst L,Muijsers AO,Skjeldal OH,Stokke O,Jakobs C,Besley GT,Wraith JE,Wanders RJ

    更新日期：1997-10-01 00:00:00

  • Conventional wisdom.

    abstract：:Recent agreement on stable reference sequences for reporting human genetic variants now allows us to mandate the use of the allele naming conventions developed by the Human Genome Variation Society. ...

    journal_title：Nature genetics

    pub_type： 社论

    doi：10.1038/ng0510-363

    authors：

    更新日期：2010-05-01 00:00:00

  • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

    abstract：:Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 ad...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.686

    authors： Speliotes EK,Willer CJ,Berndt SI,Monda KL,Thorleifsson G,Jackson AU,Lango Allen H,Lindgren CM,Luan J,Mägi R,Randall JC,Vedantam S,Winkler TW,Qi L,Workalemahu T,Heid IM,Steinthorsdottir V,Stringham HM,Weedon MN,Wheel

    更新日期：2010-11-01 00:00:00

  • Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.

    abstract：:To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = ...

    journal_title：Nature genetics

    pub_type： 杂志文章,meta分析

    doi：10.1038/ng.567

    authors： Freathy RM,Mook-Kanamori DO,Sovio U,Prokopenko I,Timpson NJ,Berry DJ,Warrington NM,Widen E,Hottenga JJ,Kaakinen M,Lange LA,Bradfield JP,Kerkhof M,Marsh JA,Mägi R,Chen CM,Lyon HN,Kirin M,Adair LS,Aulchenko YS,Benne

    更新日期：2010-05-01 00:00:00

  • Untangling the genetics from the epigenetics in pancreatic cancer metastasis.

    abstract：:Comparative genomic analyses of primary tumors and metastases within individuals with pancreatic cancer have exposed the complex clonal dynamics that underlie the dissemination of cancer cells to distant sites. Recent studies implicate non-genetic mechanisms in this process, particularly fluctuations in chromatin stat...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.3798

    authors： Vakoc CR,Tuveson DA

    更新日期：2017-02-24 00:00:00

  • Stochastic yet biased expression of multiple Dscam splice variants by individual cells.

    abstract：:The Drosophila melanogaster gene Dscam is essential for axon guidance and has 38,016 possible alternative splice forms. This diversity can potentially be used to distinguish cells. We analyzed the Dscam mRNA isoforms expressed by different cell types and individual cells. The choice of splice variants expressed is reg...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng1299

    authors： Neves G,Zucker J,Daly M,Chess A

    更新日期：2004-03-01 00:00:00

  • Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.

    abstract：:Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR-Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing b...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.3878

    authors： Tchasovnikarova IA,Timms RT,Douse CH,Roberts RC,Dougan G,Kingston RE,Modis Y,Lehner PJ

    更新日期：2017-07-01 00:00:00

  • Toward genome-wide SNP genotyping.

    abstract：:Genome-wide association studies with SNP markers are expected to allow identification of genes that underlie complex disorders. Hundreds of thousands of SNP markers will be required for comprehensive genome-wide association studies. The development of microarray-based methods for SNP genotyping on this scale remains a...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng1558

    authors： Syvänen AC

    更新日期：2005-06-01 00:00:00

  • A Y-encoded subunit of the translation initiation factor Eif2 is essential for mouse spermatogenesis.

    abstract：:In mouse and man, deletions of specific regions of the Y chromosome have been linked to early failure of spermatogenesis and consequent sterility; the Y chromosomal gene(s) with this essential early role in spermatogenesis have not been identified. The partial deletion of the mouse Y short arm (the Sxrb deletion) that...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng717

    authors： Mazeyrat S,Saut N,Grigoriev V,Mahadevaiah SK,Ojarikre OA,Rattigan A,Bishop C,Eicher EM,Mitchell MJ,Burgoyne PS

    更新日期：2001-09-01 00:00:00

  • LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.

    abstract：:The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance ...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/72807

    authors： Shackleton S,Lloyd DJ,Jackson SN,Evans R,Niermeijer MF,Singh BM,Schmidt H,Brabant G,Kumar S,Durrington PN,Gregory S,O'Rahilly S,Trembath RC

    更新日期：2000-02-01 00:00:00

  • Mouse segmental duplication and copy number variation.

    abstract：:Detailed analyses of the clone-based genome assembly reveal that the recent duplication content of mouse (4.94%) is now comparable to that of human (5.5%), in contrast to previous estimates from the whole-genome shotgun sequence assembly. However, the architecture of mouse and human genomes differs markedly: most mous...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.172

    authors： She X,Cheng Z,Zöllner S,Church DM,Eichler EE

    更新日期：2008-07-01 00:00:00

  • Human artificial episomal chromosomes for cloning large DNA fragments in human cells.

    abstract：:We have developed a human artificial episomal chromosome (HAEC) system, based on the latent replication origin of the large herpes Epstein-Barr virus, for the propagation and stable maintenance of DNA as circular minichromosomes in human cells. Individual HAECs carried human genomic inserts ranging from 60-330 kb and ...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng0994-33

    authors： Sun TQ,Fenstermacher DA,Vos JM

    更新日期：1994-09-01 00:00:00

  • Identification of DOK genes as lung tumor suppressors.

    abstract：:Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 a...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.527

    authors： Berger AH,Niki M,Morotti A,Taylor BS,Socci ND,Viale A,Brennan C,Szoke J,Motoi N,Rothman PB,Teruya-Feldstein J,Gerald WL,Ladanyi M,Pandolfi PP

    更新日期：2010-03-01 00:00:00

  • Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).

    abstract：:Hereditary multiple exostoses is an autosomal dominant disorder that is characterized by short stature and multiple, benign bone tumours. In a majority of families, the genetic defect (EXT1) is linked to the Langer-Giedion syndrome chromosomal region in 8q24.1. From this region we have cloned and characterized a cDNA ...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng1095-137

    authors： Ahn J,Lüdecke HJ,Lindow S,Horton WA,Lee B,Wagner MJ,Horsthemke B,Wells DE

    更新日期：1995-10-01 00:00:00

  • Genomic screening and replication using the same data set in family-based association testing.

    abstract：:The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. ...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng1582

    authors： Van Steen K,McQueen MB,Herbert A,Raby B,Lyon H,Demeo DL,Murphy A,Su J,Datta S,Rosenow C,Christman M,Silverman EK,Laird NM,Weiss ST,Lange C

    更新日期：2005-07-01 00:00:00

  • Requirement for Wnt3 in vertebrate axis formation.

    abstract：:Several studies have implicated Wnt signalling in primary axis formation during vertebrate embryogenesis, yet no Wnt protein has been shown to be essential for this process. In the mouse, primitive streak formation is the first overt morphological sign of the anterior-posterior axis. Here we show that Wnt3 is expresse...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/11932

    authors： Liu P,Wakamiya M,Shea MJ,Albrecht U,Behringer RR,Bradley A

    更新日期：1999-08-01 00:00:00

  • Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior.

    abstract：:Urocortin is a member of the corticotropin-releasing hormone peptide family and is found in many discrete brain regions. The distinct expression pattern of urocortin suggests that it influences such behaviors as feeding, anxiety and auditory processing. To better define the physiological roles of urocortin, we have ge...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng914

    authors： Vetter DE,Li C,Zhao L,Contarino A,Liberman MC,Smith GW,Marchuk Y,Koob GF,Heinemann SF,Vale W,Lee KF

    更新日期：2002-08-01 00:00:00

  • Isolation of chromosome 21-specific yeast artificial chromosomes from a total human genome library.

    abstract：:A new approach for the isolation of chromosome-specific subsets from a human genomic yeast artificial chromosome (YAC) library is described. It is based on the hybridization with an Alu polymerase chain reaction (PCR) probe. We screened a 1.5 genome equivalent YAC library of megabase insert size with Alu PCR products ...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng0692-222

    authors： Chumakov IM,Le Gall I,Billault A,Ougen P,Soularue P,Guillou S,Rigault P,Bui H,De Tand MF,Barillot E

    更新日期：1992-06-01 00:00:00

  • Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency.

    abstract：:All molybdoenzymes other than nitrogenase require molybdopterin as a metal-binding cofactor. Several genes necessary for the synthesis of the molybdenum cofactor (MoCo) have been characterized in bacteria and plants. The proteins encoded by the Escherichia coli genes moaA and moaC catalyse the first steps in MoCo synt...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/1706

    authors： Reiss J,Cohen N,Dorche C,Mandel H,Mendel RR,Stallmeyer B,Zabot MT,Dierks T

    更新日期：1998-09-01 00:00:00

  • An inducible long noncoding RNA amplifies DNA damage signaling.

    abstract：:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently precise regulation but mostly unknown functions. Here we demonstrate that lncRNAs guide the organismal DNA damage response. DNA damage activated transcription of the DINO (Damage Induced Noncoding) lncRNA via p53. DINO was required for p53-dependent gen...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.3673

    authors： Schmitt AM,Garcia JT,Hung T,Flynn RA,Shen Y,Qu K,Payumo AY,Peres-da-Silva A,Broz DK,Baum R,Guo S,Chen JK,Attardi LD,Chang HY

    更新日期：2016-11-01 00:00:00

  • HOXB13, RFX6 and prostate cancer risk.

    abstract：:A new study shows that HOXB13 is preferentially recruited to the risk allele of a prostate cancer-associated SNP, enhancing the expression of RFX6, a driver of prostate cancer cell migration and predictor of disease progression. The work illustrates how a single risk locus contributes both to prostate cancer incidence...

    journal_title：Nature genetics

    pub_type： 评论,杂志文章

    doi：10.1038/ng.2881

    authors： Mills IG

    更新日期：2014-02-01 00:00:00

  • Systematic assessment of copy number variant detection via genome-wide SNP genotyping.

    abstract：:SNP genotyping has emerged as a technology to incorporate copy number variants (CNVs) into genetic analyses of human traits. However, the extent to which SNP platforms accurately capture CNVs remains unclear. Using independent, sequence-based CNV maps, we find that commonly used SNP platforms have limited or no probe ...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng.236

    authors： Cooper GM,Zerr T,Kidd JM,Eichler EE,Nickerson DA

    更新日期：2008-10-01 00:00:00

  • Distinct in vivo requirements for establishment versus maintenance of transcriptional repression.

    abstract：:Low-level ectopic expression of the Runt transcription factor blocks activation of the Drosophila melanogaster segmentation gene engrailed (en) in odd-numbered parasegments and is associated with a lethal phenotype. Here we show, by using a genetic screen for maternal factors that contribute in a dose-dependent fashio...

    journal_title：Nature genetics

    pub_type： 杂志文章

    doi：10.1038/ng942

    authors： Wheeler JC,VanderZwan C,Xu X,Swantek D,Tracey WD,Gergen JP

    更新日期：2002-09-01 00:00:00