A Cell Cycle-Dependent Regulatory Circuit Composed of 53BP1-RIF1 and BRCA1-CtIP Controls DNA Repair Pathway Choice

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Highlights? 53BP1 inhibits BRCA1 recruitment to DSB sites in G1 ? RIF1 is the effector of 53BP1 during DSB repair ? Class-switch recombination requires RIF1 ? RIF1 recruitment to DSB sites in S/G2 is inhibited by BRCA1-CtIP     

c-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor

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Highlights? c-Cbl is a NEDD8 E3 ligase of TβRII ? c-Cbl neddylates TβRII at Lys556 and Lys567 ? Neddylation stabilizes TβRII by regulating receptor endocytic routes ? Aberrant neddylation of TβRII is associated with leukemia     

Adaptor protein self-assembly drives the control of a cullin-RING ubiquitin ligase

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Highlights? The crystal structure of the heterotetrameric CRL3-SPOP ubiquitin ligase is reported ? Substrate adaptor proteins are recruited to CRL complexes through a signature motif ? Tandem BTB and BACK domains potentiate assembly and activity of the CRL3-SPOP ligase ? The SPOPL negative regulator creates a molecular rheostat to fine-tune CRL3 activity     

RIF1 Is Essential for 53BP1-Dependent Nonhomologous End Joining and Suppression of DNA Double-Strand Break Resection

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Highlights? RIF1 is essential for 53BP1-dependent CSR and fusion of dysfunctional telomeres ? BRCA1 antagonizes RIF1 in S phase to prevent error-prone repair by toxic NHEJ ? N-terminal phospho-SQ/TQ domain of 53BP1 interacts with and recruits RIF1 to DSBs ? RIF1 and 53BP1 promote NHEJ in G1 by blocking 5′ end resection of DSBs     

Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression

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Highlights? Loss of mutant pVHL in VHL-associated tumors is due to rapid degradation ? Mutant pVHL maintains its intrinsic function as an E3 ligase ? HDACIs stabilize mutant pVHL and ameliorate tumor growth in vivo ? HDACIs represent a targeted therapy for VHL-associated tumors     

Adaptation of Aminoacyl-tRNA Synthetase Catalytic Core to Carrier Protein Aminoacylation

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Highlights? The crystal structure of the aa:CP ligase in complex with carrier protein was solved ? The interaction relies on the idiosyncratic α-helix of the aa:CP ligase ? The complex represents a unique mode of carrier protein recognition and binding ? The mechanism of amino acid attachment to carrier protein is discussed     

Structural Basis of Selective Ubiquitination of TRF1 by SCFFbx4

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Highlights? SCF ubiquitin ligase subunit Fbx4 binds TRF1 using an atypical small GTPase fold ? Fbx4 recognizes a globular domain of TRF1, not just short phosphorylated degrons ? Telomere shelterin component TIN2 competes with Fbx4 for TRF1 binding ? TIN2 and SCF^Fbx4 thus control TRF1 ubiquitination and degradation     

Structure of the Catalytic Region of DNA Ligase IV in Complex with an Artemis Fragment Sheds Light on Double-Strand Break Repair

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Highlights? The crystal structure of the DNA ligase IV/Artemis complex was solved at 2.4 Å ? The structure of DNA ligase IV (residues 1–609) shows inserts ? An Artemis helix forms a three-helix bundle with two helices from DNA ligase IV ? The structure provides insights into the mutations causing LIG4 syndrome     

OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function

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Highlights? Identification of OTUB1 mutants with impaired ability to inhibit E2 enzymes ? Crystal structure of a ubiquitin-charged E2 bound to OTUB1 ? Molecular basis of Lys48-linked ubiquitin chain recognition by OTUB1 determined ? OTUB1 employs product inhibition mimicry to inhibit E2 enzymes     

A Fasting-Responsive Signaling Pathway that Extends Life Span in C. elegans

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Highlights? JNK/AP-1 signaling and DAF-16 play a central role in fasting-stimulus responses ? AP-1 and DAF-16 mediate induction of fasting genes that play key roles in life-span extension ? The SCF E3 ubiquitin ligase complex is a target of fasting-responsive signaling ? Fasting enhances protein ubiquitination, causing a reduction in protein carbonylation     

Different Roles for Tet1 and Tet2 Proteins in Reprogramming-Mediated Erasure of Imprints Induced by EGC Fusion

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Highlights? EGCs can erase DNA methylation at ICRs in somatic cells after fusion ? EGCs selectively induce 5hmC accumulation at ICRs in the somatic genome ? Conversion of 5mC to 5hmC at these imprinted domains requires Tet1 ? Tet2 depletion results in delayed reprogramming by EGCs     

Viral-mediated noisy gene expression reveals biphasic E2f1 response to MYC

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Highlights? Gene expression noise is an efficient means to probe dose responses ? Variability in MYC reveals biphasic E2f1 dose response ? Modeling predicts serum attenuates E2F repression by MYC ? Biphasic expression underlies discrimination of aberrant levels of growth signaling     

IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex

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Highlights? K63-linked ubiquitination regulates IKKε innate immune and oncogenic functions ? IKKε is ubiquitinated on K30, K401, and K416 ? Ubiquitination of K30 and K401 is essential for IKKε activity and oncogene function ? A cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex binds to and modifies IKKε     

Promiscuous Interactions of gp78 E3 Ligase CUE Domain with Polyubiquitin Chains

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Highlights? The ubiquitin ligase gp78 recruits ubiquitinated substrates via its CUE domain ? gp78CUE:Ub complex reveals a large set of specific interactions ? gp78CUE binds to both distal and proximal moities of diubiquitin in a similar fashion ? The gp78CUE domain binds to K48- and K63-linked diubiquitin equally well     

Spp1, a Member of the Set1 Complex,Promotes Meiotic DSB Formation in Promoters by Tethering Histone H3K4 Methylation Sites to Chromosome Axes

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Highlights? Spp1 and histone H3K4 residue are important for meiotic DSB formation ? Spp1 physically interacts with the DSB protein Mer2 ? Spp1 in meiosis is not with RNA Pol II, but on chromosome axes in DSB-rich domains ? Spp1’s PHD finger tethers H3K4me3 regions to chromosome axes for DSB formation     

SIP1 Mediates Cell-Fate Decisions between Neuroectoderm and Mesendoderm in Human Pluripotent Stem Cells

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Highlights? Smad-interacting protein 1 (SIP1) regulates hESC differentiation ? SIP1 upregulation promotes neuroectodermal differentiation ? SIP1 inhibits mesendodermal and endodermal differentiation ? SMAD2/3 and NANOG/OCT4/SOX2 cooperatively regulate SIP1 expression     

POT1-TPP1 Regulates Telomeric Overhang Structural Dynamics

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Highlights? POT1 binds the telomere overhang sequentially one OB fold at a time ? POT1 binding exhibits 3′ to 5′ directionality ? POT1-TPP1N induces dynamic folding and unfolding of telomeric overhang ? POT1-TPP1N slides back and forth on the telomeric overhang     

Quiescent and Active Hippocampal Neural Stem Cells with Distinct Morphologies Respond Selectively to Physiological and Pathological Stimuli and Aging

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Highlights? Notch signaling defines morphologically distinct hippocampal stem cell populations ? Radial and horizontal hippocampal stem cells depend on canonical Notch signaling ? Different neural stem cell subpopulations respond selectively to neurogenic stimuli ? Aging results in a reversible transition of stem cells to a quiescent state     

The Retroviral Restriction Ability of SAMHD1, but Not Its Deoxynucleotide Triphosphohydrolase Activity,Is Regulated by Phosphorylation

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Highlights? SAMHD1 only exhibits antiviral activity when expressed in noncycling cells ? SAMHD1 is unphosphorylated in noncycling cells ? Reverse genetics revealed that phosphorylated SAMHD1 is repressive for restriction ? SAMHD1 phosphorylation regulates restriction, but not the cellular levels of dNTPs     

Pou5f1-Dependent EGF Expression Controls E-Cadherin Endocytosis,Cell Adhesion,and Zebrafish Epiboly Movements

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Highlights? Pou5f1 regulates EGF expression during oogenesis ? EGFR signaling controls E-cadherin trafficking at blastula and gastrula stages ? E-cadherin subcellular trafficking controls adhesion and cell migration ? Dynamics of E-cadherin adhesion is essential for effective cell migration