ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts.


:S(N)1-type alkylating agents that produce cytotoxic O(6)-methyl-G (O(6)-meG) DNA adducts induce cell cycle arrest and apoptosis in a manner requiring the DNA mismatch repair (MMR) proteins MutSalpha and MutLalpha. Here, we show that checkpoint signaling in response to DNA methylation occurs during S phase and requires DNA replication that gives rise to O(6)-meG/T mispairs. DNA binding studies reveal that MutSalpha specifically recognizes O(6)-meG/T mispairs, but not O(6)-meG/C. In an in vitro assay, ATR-ATRIP, but not RPA, is preferentially recruited to O(6)-meG/T mismatches in a MutSalpha- and MutLalpha-dependent manner. Furthermore, ATR kinase is activated to phosphorylate Chk1 in the presence of O(6)-meG/T mispairs and MMR proteins. These results suggest that MMR proteins can act as direct sensors of methylation damage and help recruit ATR-ATRIP to sites of cytotoxic O(6)-meG adducts to initiate ATR checkpoint signaling.


Mol Cell


Molecular cell


Yoshioka K,Yoshioka Y,Hsieh P




Has Abstract


2006-05-19 00:00:00














  • Mouse Heterochromatin Adopts Digital Compaction States without Showing Hallmarks of HP1-Driven Liquid-Liquid Phase Separation.

    abstract::The formation of silenced and condensed heterochromatin foci involves enrichment of heterochromatin protein 1 (HP1). HP1 can bridge chromatin segments and form liquid droplets, but the biophysical principles underlying heterochromatin compartmentalization in the cell nucleus are elusive. Here, we assess mechanisticall...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Erdel F,Rademacher A,Vlijm R,Tünnermann J,Frank L,Weinmann R,Schweigert E,Yserentant K,Hummert J,Bauer C,Schumacher S,Al Alwash A,Normand C,Herten DP,Engelhardt J,Rippe K

    更新日期:2020-04-16 00:00:00

  • A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.

    abstract::FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Rocchi S,Picard F,Vamecq J,Gelman L,Potier N,Zeyer D,Dubuquoy L,Bac P,Champy MF,Plunket KD,Leesnitzer LM,Blanchard SG,Desreumaux P,Moras D,Renaud JP,Auwerx J

    更新日期:2001-10-01 00:00:00

  • Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast.

    abstract::Type II topoisomerases are essential for resolving topologically entwined double-stranded DNA. Although anti-topoisomerase 2 (Top2) drugs are clinically important antibiotics and chemotherapies, to our knowledge, the mechanisms of cell killing by Top2 depletion and inactivation have never been directly compared. We sh...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Baxter J,Diffley JF

    更新日期:2008-06-20 00:00:00

  • Global Mapping of Human RNA-RNA Interactions.

    abstract::The majority of the human genome is transcribed into non-coding (nc)RNAs that lack known biological functions or else are only partially characterized. Numerous characterized ncRNAs function via base pairing with target RNA sequences to direct their biological activities, which include critical roles in RNA processing...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Sharma E,Sterne-Weiler T,O'Hanlon D,Blencowe BJ

    更新日期:2016-05-19 00:00:00

  • Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication.

    abstract::DNA replication is initiated by assembly of the kinase cell division cycle 7 (CDC7) with its regulatory activation subunit, activator of S-phase kinase (ASK), to activate DNA helicase. However, the mechanism underlying regulation of CDC7-ASK complex is unclear. Here, we show that ADP generated from CDC7-mediated MCM p...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Li X,Qian X,Jiang H,Xia Y,Zheng Y,Li J,Huang BJ,Fang J,Qian CN,Jiang T,Zeng YX,Lu Z

    更新日期:2018-11-15 00:00:00

  • Kinetochores coordinate pericentromeric cohesion and early DNA replication by Cdc7-Dbf4 kinase recruitment.

    abstract::Centromeres play several important roles in ensuring proper chromosome segregation. Not only do they promote kinetochore assembly for microtubule attachment, but they also support robust sister chromatid cohesion at pericentromeres and facilitate replication of centromeric DNA early in S phase. However, it is still el...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Natsume T,Müller CA,Katou Y,Retkute R,Gierliński M,Araki H,Blow JJ,Shirahige K,Nieduszynski CA,Tanaka TU

    更新日期:2013-06-06 00:00:00

  • Distressing bacteria: structure of a prokaryotic detox program.

    abstract::MazF and MazE are components of a chromosomal toxin-antitoxin system of Escherichia coli. In this issue of Molecular Cell, Kamada et al. describe the crystal structure of a MazE/MazF heterohexamer and propose that the mechanism of toxin-antidote recognition is common to other homologous chromosomal and plasmid-borne s...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章,评审


    authors: de la Cueva-Méndez G

    更新日期:2003-04-01 00:00:00

  • Autoadaptive ER-associated degradation defines a preemptive unfolded protein response pathway.

    abstract::Folding-defective proteins must be cleared efficiently from the endoplasmic reticulum (ER) to prevent perturbation of the folding environment and to maintain cellular proteostasis. Misfolded proteins engage dislocation machineries (dislocons) built around E3 ubiquitin ligases that promote their transport across the ER...

    journal_title:Molecular cell

    pub_type: 杂志文章,收录出版


    authors: Bernasconi R,Galli C,Kokame K,Molinari M

    更新日期:2013-12-26 00:00:00

  • Mind the Gapmer: Implications of Co-transcriptional Cleavage by Antisense Oligonucleotides.

    abstract::While gapmers efficiently knock down as well as terminate transcription of nascent lncRNAs and mRNAs, Lee and Mendell (2020) and Lai et al. (2020) also demonstrate that Pol II termination is not observed with gapmers targeting the 3' terminal portions of the transcript. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章


    authors: Maranon DG,Wilusz J

    更新日期:2020-03-05 00:00:00

  • The BCL-2 family reunion.

    abstract::B cell CLL/lymphoma-2 (BCL-2) and its relatives comprise the BCL-2 family of proteins, which were originally characterized with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis. Current observations expand BCL-2 family function to include numerous cellular pathways. Here we wi...

    journal_title:Molecular cell

    pub_type: 杂志文章,评审


    authors: Chipuk JE,Moldoveanu T,Llambi F,Parsons MJ,Green DR

    更新日期:2010-02-12 00:00:00

  • Structural basis of Rho GTPase-mediated activation of the formin mDia1.

    abstract::Diaphanous-related formins (DRFs) regulate dynamics of unbranched actin filaments during cell contraction and cytokinesis. DRFs are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain (DAD) to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GT...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Otomo T,Otomo C,Tomchick DR,Machius M,Rosen MK

    更新日期:2005-04-29 00:00:00

  • Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put.

    abstract::Chromatin modification by Polycomb proteins provides an essential strategy for gene silencing in higher eukaryotes. Polycomb repressive complexes (PRCs) silence key developmental regulators and are centrally integrated in the transcriptional circuitry of stem cells. PRC2 trimethylates histone H3 on lysine 27 (H3K27me3...

    journal_title:Molecular cell

    pub_type: 杂志文章,评审


    authors: Simon JA,Kingston RE

    更新日期:2013-03-07 00:00:00

  • An In Vitro Assembly System Identifies Roles for RNA Nucleation and ATP in Yeast Stress Granule Formation.

    abstract::Stress granules (SGs) are condensates of mRNPs that form in response to stress. SGs arise by multivalent protein-protein, protein-RNA, and RNA-RNA interactions. However, the role of RNA-RNA interactions in SG assembly remains understudied. Here, we describe a yeast SG reconstitution system that faithfully recapitulate...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Begovich K,Wilhelm JE

    更新日期:2020-09-17 00:00:00

  • A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase.

    abstract::A kinase-anchoring proteins (AKAPs) target PKA to specific microdomains by using an amphipathic helix that docks to N-terminal dimerization and docking (D/D) domains of PKA regulatory (R) subunits. To understand specificity, we solved the crystal structure of the helical motif from D-AKAP2, a dual-specific AKAP, bound...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Kinderman FS,Kim C,von Daake S,Ma Y,Pham BQ,Spraggon G,Xuong NH,Jennings PA,Taylor SS

    更新日期:2006-11-03 00:00:00

  • ChIC and ChEC; genomic mapping of chromatin proteins.

    abstract::To map the genomic interaction sites of chromatin proteins, two related methods were developed and experimentally explored in Saccharomyces cerevisiae. The ChIC method (chromatin immunocleavage) consists of tethering a fusion protein (pA-MN) consisting of micrococcal nuclease (MN) and staphylococcal protein A to speci...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Schmid M,Durussel T,Laemmli UK

    更新日期:2004-10-08 00:00:00

  • Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt.

    abstract::Forkhead box O (FOXO) transcription factors, the key regulators of cell survival, are negatively controlled through the PI3K-Akt signaling pathway. Phosphorylation of FOXO by Akt leads to cytoplasmic localization and subsequent degradation via the ubiquitin-proteasome system. Here we show a paradigm of FOXO1 regulatio...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Yamagata K,Daitoku H,Takahashi Y,Namiki K,Hisatake K,Kako K,Mukai H,Kasuya Y,Fukamizu A

    更新日期:2008-10-24 00:00:00

  • Stopping the Clock with MYC.

    abstract::In a recent paper in Cell Metabolism, Altman et al. (2015) report that MYC disrupts the molecular clock in cancer cells and describe a link between oncogenesis, circadian rhythms, and metabolism. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章


    authors: Lau AN,Vander Heiden MG

    更新日期:2015-11-19 00:00:00

  • Gcn4 Binding in Coding Regions Can Activate Internal and Canonical 5' Promoters in Yeast.

    abstract::Gcn4 is a yeast transcriptional activator induced by amino acid starvation. ChIP-seq analysis revealed 546 genomic sites occupied by Gcn4 in starved cells, representing ∼30% of Gcn4-binding motifs. Surprisingly, only ∼40% of the bound sites are in promoters, of which only ∼60% activate transcription, indicating extens...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Rawal Y,Chereji RV,Valabhoju V,Qiu H,Ocampo J,Clark DJ,Hinnebusch AG

    更新日期:2018-04-19 00:00:00

  • MicroRNA pathways modulate polyglutamine-induced neurodegeneration.

    abstract::Nine human neurodegenerative diseases are due to expansion of a CAG repeat- encoding glutamine within the open reading frame of the respective genes. Polyglutamine (polyQ) expansion confers dominant toxicity, resulting in neuronal degeneration. MicroRNAs (miRNAs) have been shown to modulate programmed cell death durin...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Bilen J,Liu N,Burnett BG,Pittman RN,Bonini NM

    更新日期:2006-10-06 00:00:00

  • Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs.

    abstract::Upon glucose restriction, eukaryotic cells upregulate oxidative metabolism to maintain homeostasis. Using genetic screens, we find that the mitochondrial serine hydroxymethyltransferase (SHMT2) is required for robust mitochondrial oxygen consumption and low glucose proliferation. SHMT2 catalyzes the first step in mito...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Minton DR,Nam M,McLaughlin DJ,Shin J,Bayraktar EC,Alvarez SW,Sviderskiy VO,Papagiannakopoulos T,Sabatini DM,Birsoy K,Possemato R

    更新日期:2018-02-15 00:00:00

  • A core complex of CPSF73, CPSF100, and Symplekin may form two different cleavage factors for processing of poly(A) and histone mRNAs.

    abstract::Metazoan histone mRNAs are unique: their pre-mRNAs contain no introns, and the mRNAs are not polyadenylated, ending instead in a conserved stem-loop structure. In Drosophila, canonical poly(A) signals are located downstream of the normal cleavage site of each histone gene and are utilized when histone 3' end formation...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Sullivan KD,Steiniger M,Marzluff WF

    更新日期:2009-05-15 00:00:00

  • PML, SUMO, and RNF4: guardians of nuclear protein quality.

    abstract::In this issue of Molecular Cell, Guo et al. (2014) report that misfolded or aggregated nuclear proteins, such as pathogenic polyQ proteins, are cleared by a SUMO-dependent quality control pathway, which involves the E3 SUMO ligase PML and the SUMO-targeted ubiquitin ligase RNF4. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章


    authors: Gärtner A,Muller S

    更新日期:2014-07-03 00:00:00

  • SLC19A1 Is an Importer of the Immunotransmitter cGAMP.

    abstract::2'3'-cyclic-GMP-AMP (cGAMP) is a second messenger that activates the antiviral stimulator of interferon genes (STING) pathway. We recently identified a novel role for cGAMP as a soluble, extracellular immunotransmitter that is produced and secreted by cancer cells. Secreted cGAMP is then sensed by host cells, elicitin...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Ritchie C,Cordova AF,Hess GT,Bassik MC,Li L

    更新日期:2019-07-25 00:00:00

  • Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing.

    abstract::Trimethylation of histone H3 on lysine 4 (H3K4me3) localizes near the 5' region of genes and is tightly associated with active loci. Several proteins, such as CHD1, BPTF, JMJD2A, and the ING tumor suppressor family, directly recognize this lysine methyl mark. However, how H3K4me3 recognition participates in active tra...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Sims RJ 3rd,Millhouse S,Chen CF,Lewis BA,Erdjument-Bromage H,Tempst P,Manley JL,Reinberg D

    更新日期:2007-11-30 00:00:00

  • Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest.

    abstract::Autophagy, a catabolic pathway that delivers cellular components to lysosomes for degradation, can be activated by stressful conditions such as nutrient starvation and endoplasmic reticulum (ER) stress. We report that thapsigargin, an ER stressor widely used to induce autophagy, in fact blocks autophagy. Thapsigargin ...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Ganley IG,Wong PM,Gammoh N,Jiang X

    更新日期:2011-06-24 00:00:00

  • A Regulatory Module Controlling Homeostasis of a Plant Immune Kinase.

    abstract::Plant pattern recognition receptors (PRRs) perceive microbial and endogenous molecular patterns to activate immune signaling. The cytoplasmic kinase BIK1 acts downstream of multiple PRRs as a rate-limiting component, whose phosphorylation and accumulation are central to immune signal propagation. Previous work identif...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Wang J,Grubb LE,Wang J,Liang X,Li L,Gao C,Ma M,Feng F,Li M,Li L,Zhang X,Yu F,Xie Q,Chen S,Zipfel C,Monaghan J,Zhou JM

    更新日期:2018-02-01 00:00:00

  • Insights into FlaI functions in archaeal motor assembly and motility from structures, conformations, and genetics.

    abstract::Superfamily ATPases in type IV pili, type 2 secretion, and archaella (formerly archaeal flagella) employ similar sequences for distinct biological processes. Here, we structurally and functionally characterize prototypical superfamily ATPase FlaI in Sulfolobus acidocaldarius, showing FlaI activities in archaeal swimmi...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Reindl S,Ghosh A,Williams GJ,Lassak K,Neiner T,Henche AL,Albers SV,Tainer JA

    更新日期:2013-03-28 00:00:00

  • Spoon-Feeding Ribosomes to Autophagy.

    abstract::The ribosome, a ribonucleoprotein machine for protein synthesis, can also serve as an abundant nutrient source under starvation conditions. In a recent issue of Science, Wyant et al. (2018) discovered a specialized "spoon" to "scoop up" more ribosomes for degradation by autophagy. ...

    journal_title:Molecular cell

    pub_type: 评论,杂志文章


    authors: Nakatogawa H

    更新日期:2018-07-19 00:00:00

  • RRM Transcription Factors Interact with NLRs and Regulate Broad-Spectrum Blast Resistance in Rice.

    abstract::Nucleotide-binding site leucine-rich repeat (NLR) receptors perceive pathogen effectors and trigger plant immunity. However, the mechanisms underlying NLR-triggered defense responses remain obscure. The recently discovered Pigm locus in rice encodes a cluster of NLRs, including PigmR, which confers broad-spectrum resi...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Zhai K,Deng Y,Liang D,Tang J,Liu J,Yan B,Yin X,Lin H,Chen F,Yang D,Xie Z,Liu JY,Li Q,Zhang L,He Z

    更新日期:2019-06-06 00:00:00

  • Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha.

    abstract::The signal transducers of the transforming growth factor beta (TGFbeta)/bone morphogenetic protein (BMP), the Smads, promote the expression of a subset of miRNAs by facilitating the cleavage reaction by Drosha. The mechanism that limits Smad-mediated processing to a selective group of miRNAs remained hitherto unexplor...

    journal_title:Molecular cell

    pub_type: 杂志文章


    authors: Davis BN,Hilyard AC,Nguyen PH,Lagna G,Hata A

    更新日期:2010-08-13 00:00:00