A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.

Abstract:

:While biallelic mutations in the PALB2 tumor suppressor cause Fanconi anemia subtype FA-N, monoallelic mutations predispose to breast and familial pancreatic cancer. Although hundreds of missense variants in PALB2 have been identified in patients to date, only a few have clear functional and clinical relevance. Herein, we investigate the effects of 44 PALB2 variants of uncertain significance found in breast cancer patients and provide detailed analysis by systematic functional assays. Our comprehensive functional analysis reveals two hotspots for potentially deleterious variations within PALB2, one at each terminus. PALB2 N-terminus variants p.P8L [c.23C>T], p.Y28C [c.83A>G], and p.R37H [c.110G>A] compromised PALB2-mediated homologous recombination. At the C-terminus, PALB2 variants p.L947F [c.2841G>T], p.L947S [c.2840T>C], and most strikingly p.T1030I [c.3089C>T] and p.W1140G [c.3418T>C], stood out with pronounced PARP inhibitor sensitivity and cytoplasmic accumulation in addition to marked defects in recruitment to DNA damage sites, interaction with BRCA2 and homologous recombination. Altogether, our findings show that a combination of functional assays is necessary to assess the impact of germline missense variants on PALB2 function, in order to guide proper classification of their deleteriousness.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Rodrigue A,Margaillan G,Torres Gomes T,Coulombe Y,Montalban G,da Costa E Silva Carvalho S,Milano L,Ducy M,De-Gregoriis G,Dellaire G,Araújo da Silva W Jr,Monteiro AN,Carvalho MA,Simard J,Masson JY

doi

10.1093/nar/gkz780

subject

Has Abstract

pub_date

2019-11-18 00:00:00

pages

10662-10677

issue

20

eissn

0305-1048

issn

1362-4962

pii

5581727

journal_volume

47

pub_type

杂志文章
  • MicroRNA-mediated up-regulation of an alternatively polyadenylated variant of the mouse cytoplasmic {beta}-actin gene.

    abstract::Actin is a major cytoskeletal protein in eukaryotes. Recent studies suggest more diverse functional roles for this protein. Actin mRNA is known to be localized to neuronal synapses and undergoes rapid deadenylation during early developmental stages. However, its 3'-untranslated region (UTR) is not characterized and th...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkn624

    authors: Ghosh T,Soni K,Scaria V,Halimani M,Bhattacharjee C,Pillai B

    更新日期:2008-11-01 00:00:00

  • Alkylation of template strand of coding region causes effective gene silencing.

    abstract::We recently developed a new type of pyrrole (Py)-imidazole (Im) polyamide-tetrahydrocyclopropabenzindolone (CBI) conjugate with an indole linker as a stable sequence-specific alkylating agent. In this study, we investigated the gene silencing activities of polyamides A, B and C, which selectively alkylate specific seq...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkl005

    authors: Shinohara K,Sasaki S,Minoshima M,Bando T,Sugiyama H

    更新日期:2006-02-25 00:00:00

  • COMPASS server for remote homology inference.

    abstract::COMPASS is a method for homology detection and local alignment construction based on the comparison of multiple sequence alignments (MSAs). The method derives numerical profiles from given MSAs, constructs local profile-profile alignments and analytically estimates E-values for the detected similarities. Until now, CO...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkm293

    authors: Sadreyev RI,Tang M,Kim BH,Grishin NV

    更新日期:2007-07-01 00:00:00

  • The Wilms' tumor suppressor gene (wt1) product represses different functional classes of transcriptional activation domains.

    abstract::We have studied the ability of the wt1 tumor suppressor gene product to repress different classes of activation domains previously shown to stimulate the initiation and elongation steps of RNA polymerase II transcription in vivo. Repression assays revealed that WT1 represses all three classes of activation domains: Sp...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/27.14.2889

    authors: Lee TH,Moffett P,Pelletier J

    更新日期:1999-07-15 00:00:00

  • Major capsid reinforcement by a minor protein in herpesviruses and phage.

    abstract::Herpes simplex type 1 virus (HSV-1) and bacteriophage λ capsids undergo considerable structural changes during self-assembly and DNA packaging. The initial steps of viral capsid self-assembly require weak, non-covalent interactions between the capsid subunits to ensure free energy minimization and error-free assembly....

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gku634

    authors: Sae-Ueng U,Liu T,Catalano CE,Huffman JB,Homa FL,Evilevitch A

    更新日期:2014-08-01 00:00:00

  • De novo assembly of genuine replication forks on an immobilized circular plasmid in Xenopus egg extracts.

    abstract::We describe an improved model of DNA replication in Xenopus egg extracts, in which a circular plasmid immobilized on paramagnetic beads is used as a template. DNA synthesis occurred on either circular or linear plasmids coupled to the beads, but only DNA synthesis on the circular plasmid was inhibited by geminin and a...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkl512

    authors: Zembutsu A,Waga S

    更新日期:2006-07-26 00:00:00

  • Zinc ions are differentially required for the transcription of ribosomal 5S RNA and tRNA in a HeLa-cell extract.

    abstract::Chelation of divalent cations by 5 mM EDTA and subsequent removal by dialysis from a cytoplasmic HeLa cell extract leads to a complete loss of 5S rRNA transcription without affecting tRNA synthesis. Transcription complexes for 5S RNA can no longer be assembled in such a zinc-depleted extract and this ability can be fu...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/12.23.8971

    authors: Wingender E,Dilloo D,Seifart KH

    更新日期:1984-12-11 00:00:00

  • Identifying functional gene sets from hierarchically clustered expression data: map of abiotic stress regulated genes in Arabidopsis thaliana.

    abstract::We present MultiGO, a web-enabled tool for the identification of biologically relevant gene sets from hierarchically clustered gene expression trees (http://ekhidna.biocenter.helsinki.fi/poxo/multigo). High-throughput gene expression measuring techniques, such as microarrays, are nowadays often used to monitor the exp...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkl694

    authors: Kankainen M,Brader G,Törönen P,Palva ET,Holm L

    更新日期:2006-01-01 00:00:00

  • Primary and secondary structures of chicken, rat and man nuclear U4 RNAs. Homologies with U1 and U5 RNAs.

    abstract::U4 RNA from chicken, rat and man was examined for nucleotide sequence and secondary structure. Three molecular species, U4A, U4B and U4C were detected in the three animal species. U4A is 146 nucleotide long and U4B RNA only lacks the 3' terminal G. four nucleotides are missing at the 3'-end of U4C RNA which, in additi...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/9.12.2699

    authors: Krol A,Branlant C,Lazar E,Gallinaro H,Jacob M

    更新日期:1981-06-25 00:00:00

  • mrsFAST-Ultra: a compact, SNP-aware mapper for high performance sequencing applications.

    abstract::High throughput sequencing (HTS) platforms generate unprecedented amounts of data that introduce challenges for processing and downstream analysis. While tools that report the 'best' mapping location of each read provide a fast way to process HTS data, they are not suitable for many types of downstream analysis such a...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gku370

    authors: Hach F,Sarrafi I,Hormozdiari F,Alkan C,Eichler EE,Sahinalp SC

    更新日期:2014-07-01 00:00:00

  • Transgenic zebrafish model to study translational control mediated by upstream open reading frame of human chop gene.

    abstract::Upstream open reading frame (uORF)-mediated translational inhibition is important in controlling key regulatory genes expression. However, understanding the underlying molecular mechanism of such uORF-mediated control system in vivo is challenging in the absence of an animal model. Therefore, we generated a zebrafish ...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkr645

    authors: Lee HC,Chen YJ,Liu YW,Lin KY,Chen SW,Lin CY,Lu YC,Hsu PC,Lee SC,Tsai HJ

    更新日期:2011-11-01 00:00:00

  • Hierarchy and positive/negative interplays of the hepatocyte nuclear factors HNF-1, -3 and -4 in the liver-specific enhancer for the human alpha-1-microglobulin/bikunin precursor.

    abstract::Alpha-1-microglobulin and bikunin are two plasma glycoproteins encoded by an alpha-1-microglobulin/bikunin precursor (AMBP) gene. The strict liver-specific expression of the AMBP gene is controlled by a potent enhancer made of six clustered boxes numbered 1-6 that have been reported to be proven or potential binding s...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/23.3.395

    authors: Rouet P,Raguenez G,Tronche F,Mfou'ou V,Salier JP

    更新日期:1995-02-11 00:00:00

  • ModBase, a database of annotated comparative protein structure models, and associated resources.

    abstract::ModBase (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by ModPipe, an automated modeling pipeline that relies primarily on Modeller for fold assignment, sequence-structure alignment, model building and model assessment (http://salilab.org/modelle...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkq1091

    authors: Pieper U,Webb BM,Barkan DT,Schneidman-Duhovny D,Schlessinger A,Braberg H,Yang Z,Meng EC,Pettersen EF,Huang CC,Datta RS,Sampathkumar P,Madhusudhan MS,Sjölander K,Ferrin TE,Burley SK,Sali A

    更新日期:2011-01-01 00:00:00

  • Peptidyl-tRNA hydrolase from Sulfolobus solfataricus.

    abstract::An enzyme capable of liberating functional tRNA(Lys) from Escherichia coli diacetyl-lysyl-tRNA(Lys) was purified from the archae Sulfolobus solfataricus. Contrasting with the specificity of peptidyl- tRNA hydrolase (PTH) from E.coli, the S.solfataricus enzyme readily accepts E.coli formyl-methionyl-tRNA(fMet) as a sub...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkg428

    authors: Fromant M,Ferri-Fioni ML,Plateau P,Blanquet S

    更新日期:2003-06-15 00:00:00

  • Synthetic switch to minimize CRISPR off-target effects by self-restricting Cas9 transcription and translation.

    abstract::CRISPR/Cas9 is a powerful genome editing system but uncontrolled Cas9 nuclease expression triggers off-target effects and even in vivo immune responses. Inspired by synthetic biology, here we built a synthetic switch that self-regulates Cas9 expression not only in the transcription step by guide RNA-aided self-cleavag...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gky1165

    authors: Shen CC,Hsu MN,Chang CW,Lin MW,Hwu JR,Tu Y,Hu YC

    更新日期:2019-02-20 00:00:00

  • Alteration of the DNA double helix conformation upon incorporation of mispairs as revealed by energy computations and pathways of point mutations.

    abstract::To explain biochemical and genetic data on spontaneous nucleotide replacements in nucleic acid biosynthesis all the 8 mispairs in normal tautomeric forms have been considered. Possible B-conformations of DNA fragments containing each of such mispairs incorporated between Watson-Crick pairs have been found using comput...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/13.1.141

    authors: Chuprina VP,Poltev VI

    更新日期:1985-01-11 00:00:00

  • CTdatabase: a knowledge-base of high-throughput and curated data on cancer-testis antigens.

    abstract::The potency of the immune response has still to be harnessed effectively to combat human cancers. However, the discovery of T-cell targets in melanomas and other tumors has raised the possibility that cancer vaccines can be used to induce a therapeutically effective immune response against cancer. The targets, cancer-...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkn673

    authors: Almeida LG,Sakabe NJ,deOliveira AR,Silva MC,Mundstein AS,Cohen T,Chen YT,Chua R,Gurung S,Gnjatic S,Jungbluth AA,Caballero OL,Bairoch A,Kiesler E,White SL,Simpson AJ,Old LJ,Camargo AA,Vasconcelos AT

    更新日期:2009-01-01 00:00:00

  • Interactions of Hg(II) ions with DNA as revealed by CD measurements.

    abstract::The circular dichroism spectra of Hg(II) complexes with native calf thymus DNA, chemically methylated Streptomyces chrysomallus DNA and with Ag(I)-DNA complexes were measured in the region of 220 - 340 nm. As a main result a conversion of the conservative CD spectrum of DNA to a distinct nonconservative type of CD spe...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/4.3.539

    authors: Walter A,Luck G

    更新日期:1977-03-01 00:00:00

  • Ionic strength effects on the stability and conformation of Penicillium chrysogenum mycophage double stranded RNA.

    abstract::The effect of [Na+] on the stability and conformation of penicillium chrysogenum mycophage dsRNA (PCMdsRNA) was investigated using CD and UV optical techniques. Thermal melting profiles reveal prominent fine structure attributed to at least four regions of structural dissimilarity. A constant increased thermal stabili...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/2.6.759

    authors: Burnett JP,Frank BH,Douthart RJ

    更新日期:1975-06-01 00:00:00

  • Building a livestock genetic and genomic information knowledgebase through integrative developments of Animal QTLdb and CorrDB.

    abstract::Successful development of biological databases requires accommodation of the burgeoning amounts of data from high-throughput genomics pipelines. As the volume of curated data in Animal QTLdb (https://www.animalgenome.org/QTLdb) increases exponentially, the resulting challenges must be met with rapid infrastructure dev...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gky1084

    authors: Hu ZL,Park CA,Reecy JM

    更新日期:2019-01-08 00:00:00

  • Spectroscopic studies of (m5dC-dG)3: thermal stability of B- and Z-forms.

    abstract::The hexanucleoside pentaphosphate d(m5CpGpm5CpGpm5CpG) has been studied in solution by ultra-violet absorption, circular dichroism and 31P nuclear magnetic resonance under various experimental conditions. In 0.2 M NaClO4 at low temperature, an hexamer duplex is formed which has a B or B-like conformation. As the salt ...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/11.13.4453

    authors: Hartmann B,Thuong NT,Pouyet J,Ptak M,Leng M

    更新日期:1983-07-11 00:00:00

  • G-quadruplex formation in human telomeric (TTAGGG)4 sequence with complementary strand in close vicinity under molecularly crowded condition.

    abstract::Chromosomes in vertebrates are protected at both ends by telomere DNA composed of tandem (TTAGGG)n repeats. DNA replication produces a blunt-ended leading strand telomere and a lagging strand telomere carrying a single-stranded G-rich overhang at its end. The G-rich strand can form G-quadruplex structure in the presen...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkm203

    authors: Kan ZY,Lin Y,Wang F,Zhuang XY,Zhao Y,Pang DW,Hao YH,Tan Z

    更新日期:2007-01-01 00:00:00

  • Cloning and expression of cDNA encoding mouse tyrosinase.

    abstract::We have isolated a pigment cell-specific cDNA clone from a B16 mouse melanoma cDNA library by differential hybridization. The mRNA of isolated cDNA is highly expressed in B16 melanoma cells and in black mouse (C57BL/6) skin, but is not detectable in mouse neuroblastoma cells nor in K1735 mouse amelanotic melanoma cell...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/14.6.2413

    authors: Shibahara S,Tomita Y,Sakakura T,Nager C,Chaudhuri B,Müller R

    更新日期:1986-03-25 00:00:00

  • Intron mobility in phage T4 is dependent upon a distinctive class of endonucleases and independent of DNA sequences encoding the intron core: mechanistic and evolutionary implications.

    abstract::Although mobility of the phylogenetically widespread group I introns appears to be mechanistically similar, the phage T4 intron-encoded endonucleases that promote mobility of the td and sunY introns are different from their eukaryotic counterparts. Most notably, they cleave at a distance from the intron insertion site...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/18.13.3763

    authors: Bell-Pedersen D,Quirk S,Clyman J,Belfort M

    更新日期:1990-07-11 00:00:00

  • Electrochemical detection of mismatched DNA using a MutS probe.

    abstract::A direct and label-free electrochemical biosensor for the detection of the protein-mismatched DNA interaction was designed using immobilized N-terminal histidine tagged Escherichia coli. MutS on a Ni-NTA coated Au electrode. General electrochemical methods, cyclic voltammetry (CV), electrochemical quartz crystal micro...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkl364

    authors: Cho M,Lee S,Han SY,Park JY,Rahman MA,Shim YB,Ban C

    更新日期:2006-06-13 00:00:00

  • INTERSPIA: a web application for exploring the dynamics of protein-protein interactions among multiple species.

    abstract::Proteins perform biological functions through cascading interactions with each other by forming protein complexes. As a result, interactions among proteins, called protein-protein interactions (PPIs) are not completely free from selection constraint during evolution. Therefore, the identification and analysis of PPI c...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gky378

    authors: Kwon D,Lee D,Kim J,Lee J,Sim M,Kim J

    更新日期:2018-07-02 00:00:00

  • Solution structure of a novel zinc finger motif in the SAP30 polypeptide of the Sin3 corepressor complex and its potential role in nucleic acid recognition.

    abstract::Giant chromatin-modifying complexes regulate gene transcription in eukaryotes by acting on chromatin substrates and 'setting' the histone code. The histone deacetylase (HDAC)-associated mammalian Sin3 corepressor complex regulates a wide variety of genes involved in all aspects of cellular physiology. The recruitment ...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkp051

    authors: He Y,Imhoff R,Sahu A,Radhakrishnan I

    更新日期:2009-04-01 00:00:00

  • Differences in the phosphate oxygen requirements for self-cleavage by the extended and prototypical hammerhead forms.

    abstract::The hammerhead self-cleaving motif occurs in a variety of RNAs that infect plants and consists of three non-conserved helices connected by a highly conserved central core. A variant hammerhead, called the extended hammerhead, is found in satellite 2 transcripts from a variety of caudate amphibians. The extended hammer...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/25.11.2189

    authors: Mitrasinovic O,Epstein LM

    更新日期:1997-06-01 00:00:00

  • JProGO: a novel tool for the functional interpretation of prokaryotic microarray data using Gene Ontology information.

    abstract::A novel program suite was implemented for the functional interpretation of high-throughput gene expression data based on the identification of Gene Ontology (GO) nodes. The focus of the analysis lies on the interpretation of microarray data from prokaryotes. The three well established statistical methods of the thresh...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/gkl329

    authors: Scheer M,Klawonn F,Münch R,Grote A,Hiller K,Choi C,Koch I,Schobert M,Härtig E,Klages U,Jahn D

    更新日期:2006-07-01 00:00:00

  • Synthesis and biological evaluation of some phosphate triester derivatives of the anti-cancer drug araC.

    abstract::A number of novel phosphate triester derivatives of the anti-cancer nucleoside analogue araC have been prepared by a rapid 2-step procedure, not necessitating prior sugar protection. Spectroscopic and lipophilicity data have been collected on these compounds. An in vitro assay indicated inhibition of thymidine incorpo...

    journal_title:Nucleic acids research

    pub_type: 杂志文章

    doi:10.1093/nar/17.18.7195

    authors: Jones BC,McGuigan C,Riley PA

    更新日期:1989-09-25 00:00:00