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Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis

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DEVELOPMENTAL CELL 2022年第20期57卷 2381-+页

作者： Qian, Xuyu DeGennaro, Ellen M. Talukdar, Maya Akula, Shyam K. Lai, Abbe Shao, Diane D. Gonzalez, Dilenny Marciano, Jack H. Smith, Richard S. Hylton, Norma K. Yang, Edward Bazan, J. Fernando Barrett, Lee Yeh, Rebecca C. Hill, R. Sean Beck, Samantha G. Otani, Aoi Angad, Jolly mitani, Tadahiro Posey, Jennifer E. Pehlivan, Davut Calame, Daniel Aydin, Hatip Yesilbas, Osman Parks, Kendall C. Argilli, Emanuela England, Eleina Im, Kiho Taranath, Ajay Scott, Hamish S. Barnett, Christopher P. Arts, Peer Sherr, Elliott H. Lupski, James R. Walsh, Christopher A. Harvard Med Sch Boston Childrens Hosp Div Genet & Genom Boston MA 02115 USA Harvard Med Sch Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Allen Discovery Ctr Human Brain Evolut Boston Childrens Hosp Harvard Med Sch Boston MA 02115 USA MIT Div Hlth Sci & Technol Cambridge MA 02142 USA Harvard Med Sch MD PhD Program Program Neurosci Harvard Boston MA 02115 USA Boston Childrens Hosp Dept Neurol Boston MA 02115 USA Boston Childrens Hosp Dept Radiol Boston MA 02115 USA Bioconsulting LLC Stillwater MN 55082 USA Boston Childrens Hosp Harvard Med Sch Dept Neurobiol Boston MA 02115 USA Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Baylor Coll Med Dept Pediat Houston TX 77030 USA Texas Childrens Hosp Houston TX 77030 USA Baylor Coll Med Dept Pediat Sect Pediat Neurol & Dev Neurosci Houston TX 77030 USA Zeynep Kamil Matern & Childrens Training & Res Hos Ctr Genet Diag Istanbul Turkey Karadeniz Tech Univ Fac Med Dept Pediat Div Pediat Crit Care Med TR-61080 Trabzon Turkey Univ Calif San Francisco Dept Neurol San Francisco CA 94143 USA Broad Inst & Harvard Ctr Mendelian Genom Program Med & Populat Genet Cambridge MA 02142 USA Harvard Med Sch Boston Childrens Hosp Div Newborn Med Boston MA 02115 USA Womens & Childrens Hosp Dept Med Imaging South Australia Med Imaging North Adelaide SA Australia Alliance SA Pathol & Univ South Australia Ctr Canc Biol Dept Genet & Mol Pathol Adelaide SA Australia Univ Adelaide Adelaide Med Sch Adelaide SA Australia Alliance SA Pathol & Univ South Australia Ctr Canc Biol ACRF Canc Genom Facil Adelaide SA Australia Australian Genom Parkville Vic Australia Womens & Childrens Hosp Pediat & Reprod Genet Unit North Adelaide SA Australia Univ Calif San Francisco Inst Human Genet Weill Inst Neurosci San Francisco CA 94143 USA Baylor Coll Med Human Genome Sequencing Ctr Houston TX 77030 USA

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)-and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, ex-hibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially ex-pressed during early-and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived or-ganoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed tran-scriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

关键词： congenital brain malformation development cerebral cortex corpus callosum organoid genetics kinesin migration apoptosis

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PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson's disease

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MOLECULAR NEURODEGENERATION 2020年第1期15卷 20-20页

作者： Ge, Preston Dawson, Valina L. Dawson, Ted M. Johns Hopkins Univ Neuroregenerat & Stem Cell Programs Solomon H Snyder Dept NeurosciSch MedDept Physi Inst Cell EngnDept Pharmacol & Mol SciDept Neur 733 North BroadwaySuite 731 Baltimore MD 21205 USA Adrienne Helis Malvin Med Res Fdn New Orleans LA 70130 USA Diana Helis Henry Med Res Fdn New Orleans LA 70130 USA MIT Dept Brain & Cognit Sci E25-618 Cambridge MA 02139 USA Picower Inst Learning & Memory Cambridge MA 02139 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA

That certain cell types in the central nervous system are more likely to undergo neurodegeneration in Parkinson's disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons in the substantia nigra pars compacta, have a shared phenotype of large, widely distributed axonal networks, dense synaptic connections, and high basal levels of neural activity. These features come at substantial bioenergetic cost, suggesting that these neurons experience a high degree of mitochondrial stress. In such a context, mechanisms of mitochondrial quality control play an especially important role in maintaining neuronal survival. In this review, we focus on understanding the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson's and summarize evidence that mitochondrial dysfunction contributes to disease pathogenesis and to cell death in these subpopulations. We then review mechanisms of mitochondrial quality control mediated by activation of PINK1 and Parkin, two genes that carry mutations associated with autosomal recessive Parkinson's disease. We conclude by pinpointing critical gaps in our knowledge of PINK1 and Parkin function, and propose that understanding the connection between the mechanisms of sporadic Parkinson's and defects in mitochondrial quality control will lead us to greater insights into the question of selective vulnerability.

关键词： Parkinson disease Parkin PINK1 mitochondria mitophagy Selective vulnerability Substantia nigra

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ABL1 and ABL2 promote medulloblastoma leptomeningeal dissemination

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NEURO-ONCOLOGY ADVANCES 2023年第1期5卷 vdad095页

作者： Jones, Jill K. Zhang, Hengshan Lyne, Anne-Marie Cavalli, Florence M. G. Hassen, Wafa E. Stevenson, Kevin Kornahrens, Reb Yang, Yuanfan Li, Sean Dell, Samuel Reitman, Zachary J. Herndon, James E. Hoj, Jacob Pendergast, Ann Marie Thompson, Eric M. Harvard MIT MD PhD Program Boston MA USA Duke Univ Dept Neurosurg Durham NC USA PSL Res Univ Inst Curie Paris France Inserm U900 Paris France PSL Res Univ MINES ParisTech CBI Ctr Computat Biol Paris France Duke Univ Mol Physiol Inst Durham NC USA Univ Alabama Birmingham Dept Neurosurg Birmingham AL USA Case Western Univ Sch Med Cleveland OH USA Duke Canc Inst Div Hematol Malignancies & Cellular Therapy Durham NC USA Duke Univ Sch Med Dept Radiat Oncol Durham NC USA Duke Univ Sch Med Dept Biostat & Bioinformat Durham NC USA Duke Univ Dept Pharmacol & Canc Biol Durham NC USA Duke Univ Preston Robert Brain Tumor Ctr Durham NC USA Univ Chicago Dept Neurosurg Chicago IL USA 5841 S Maryland Ave MC 3026 Chicago IL 60637 USA

Background Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (Lmd) of medulloblastoma both portends a poorer prognosis at diagnosis and is incurable at recurrence. The biological mechanisms underlying Lmd are unclear. The Abelson (ABL) tyrosine kinase family members, ABL1 and ABL2, have been implicated in cancer cell migration, invasion, adhesion, metastasis, and chemotherapy resistance, and are upstream mediators of the oncogene c-MYC in fibroblasts and lung cancer cells. However, their role in medulloblastoma has not yet been explored. The purpose of this work was to elucidate the role of ABL1/2 in medulloblastoma *** ABL1 and ABL2 mRNA expression of patient specimens was analyzed. shRNA knockdowns of ABL1/2 and pharmacologic inhibition of ABL1/2 were used for in vitro and in vivo analyses of medulloblastoma Lmd. RNA sequencing of ABL1/2 genetic knockdown versus scrambled control medulloblastoma was *** ABL1/2 mRNA is highly expressed in human medulloblastoma and pharmacologic inhibition of ABL kinases resulted in cytotoxicity. Knockdown of ABL1/2 resulted in decreased adhesion of medulloblastoma cells to the extracellular matrix protein, vitronectin (P = .0013), and significantly decreased tumor burden in a mouse model of medulloblastoma Lmd with improved overall survival (P = .0044). Furthermore, both pharmacologic inhibition of ABL1/2 and ABL1/2 knockdown resulted in decreased expression of c-MYC, identifying a putative signaling pathway, and genes/pathways related to oncogenesis and neurodevelopment were differentially expressed between ABL1/2 knockdown and control medulloblastoma *** ABL1 and ABL2 have potential roles in medulloblastoma Lmd upstream of c-MYC expression.

关键词： ABL1 ABL2 c-MYC medulloblastoma metastases

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Innovative vaccine approaches-a Keystone Symposia report

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 2022年第1期1511卷 59-86页

作者： Cable, Jennifer Rappuoli, Rino Klemm, Elizabeth J. Kang, Gagandeep Mutreja, Ankur Wright, Gavin J. Pizza, Mariagrazia Castro, Sowmya Ajay Hoffmann, Joseph P. Alter, Galit Carfi, Andrea Pollard, Andrew J. Krammer, Florian Gupta, Ravindra K. Wagner, Caroline E. Machado, Viviane Modjarrad, Kayvon Corey, Lawrence Gilbert, Peter B. Dougan, Gordon Lurie, Nicole Bjorkman, Pamela J. Chiu, Christopher Nemes, Elisa Gordon, Stephen B. Steer, Andrew C. Rudel, Thomas Blish, Catherine A. Sandberg, John Tyler Brennan, Kiva Klugman, Keith P. Stuart, Lynda M. Madhi, Shabir A. Karp, Christopher L. PhD Sci Writer New York NY 10022 USA GSK Siena Italy Wellcome Trust Res Labs London England Christian Med Coll & Hosp Div Gastrointestinal Sci Vellore Tamil Nadu India Univ Cambridge Cambridge Inst Therapeut Immunol & Infect Dis CIT Cambridge England Univ Cambridge Dept Med Cambridge England Wellcome Sanger Inst Cell Surface Signalling Lab Hinxton England Univ York Hull York Med Sch Dept Biol York N Yorkshire England Univ York York Biomed Res Inst York N Yorkshire England Univ Dundee Sch Life Sci Div Mol Microbiol Dundee Scotland Tulane Univ Sch Med Dept Pediat Ctr Translat Res Infect & Inflammat New Orleans LA 70112 USA Harvard Med Sch Ragon Inst MGH MIT & Harvard Cambridge MA USA Harvard Med Sch Massachusetts Gen Hosp Div Infect Dis Boston MA 02115 USA Moderna Inc Cambridge MA USA Univ Oxford Dept Paediat Oxford Vaccine Grp Oxford England Oxford Biomed Res Ctr Natl Inst Hlth Res NIHR Oxford England Icahn Sch Med Mt Sinai Tisch Canc Inst New York NY 10029 USA Icahn Sch Med Mt Sinai Dept Pathol New York NY 10029 USA Africa Hlth Res Inst Durban South Africa McGill Univ Dept Bioengn Montreal PQ Canada Fiocruz MS Measles & Resp Viruses Lab Oswaldo Cruz Inst WHO NIC Rio De Janeiro Brazil Walter Reed Army Inst Res Emerging Infect Dis Branch Silver Spring MD USA Univ Washington Sch Med Dept Lab Med & Pathol Seattle WA USA Univ Washington Sch Med Dept Med Seattle WA 98195 USA Fred Hutchinson Canc Res Ctr Vaccine & Infect Dis Div 1124 Columbia St Seattle WA 98104 USA Coalit Epidem Preparedness Innovat Oslo Norway Harvard Med Sch Boston MA 02115 USA CALTECH Div Biol & Biol Engn Pasadena CA 91125 USA Imperial Coll London Dept Infect Dis London England Univ Cape Town Inst Infect Dis & Mol Med Dept Pathol Div ImmunolSouth African TB Vaccine Initiat Cape Town South Africa Malawi Liverpool Wellcome Res Programme Blantyre Malawi Murdoch Childrens Res Inst Infect & Immun Parkville Vic Australia Univ Melbourne Dept Paediat

The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28-30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium "Innovative Vaccine Approaches" to discuss advances in vaccine research and development.

关键词： correlates of protection COVID-19 human challenge studies influenza pneumococcal disease streptococcus vaccines vaccine equity

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Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4^CRBN activity

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BLOOD 2018年第12期132卷 1293-1303页

作者： Sievers, Quinlan L. Gasser, Jessica A. Cowley, Glenn S. Fischer, Eric S. Ebert, Benjamin L. Broad Inst MIT & Harvard Cambridge MA USA Harvard Med Sch Brigham & Womens Hosp Div Hematol Boston MA USA Harvard Med Sch MD PhD Program Boston MA USA Dana Farber Canc Inst Dept Chem Biol Boston MA 02115 USA Harvard Med Sch Dept Biol Chem & Mol Pharmacol Boston MA USA Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA

Lenalidomide mediates the ubiquitination and degradation of Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and casein kinase 1 alpha (CK1 alpha) by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4(CRBN) E3 ubiquitin ligase. Through this mechanism, lenalidomide is a clinically effective treatment of multiple myeloma and myelodysplastic syndrome (mdS) with deletion of chromosome 5q [del(5q) mdS]. To identify the cellular machinery required for lenalidomide-induced CRL4(CRBN) activity, we performed a positive selection, genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) screen in a lenalidomide-sensitive myeloma cell line. CRBN was the top-ranking gene, with all CRBN-targeting guide RNAs (gRNAs) ranking as the 6 highest-scoring gRNAs. A counterscreen using an IKZF3 degron reporter to assay lenalidomide-induced protein degradation highlighted regulators of cullin-RING ligase neddylation and 2 E2 ubiquitin-conjugating enzymes as necessary for efficient lenalidomide-induced protein degradation. We demonstrated that loss of UBE2M or members of the constitutive photomorphogenesis 9 (COP9) signalosome results in altered neddylation of cullin 4A and impairs lenalidomide-dependent CRL4(CRBN) activity. Additionally, we established that UBE2D3 and UBE2G1 play distinct roles in substrate ubiquitination by CRL4(CRBN), with UBE2D3 acting to prime targets via monoubiquitination and UBE2G1 functioning to extend polyubiquitin chains with lysine 48 linkages. The validation of UBE2D3 and UBE2G1 highlights the functional capacity of CRISPR-Cas9 screening to identify E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase complex pairings. More broadly, these findings establish key proteins required for lenalidomide-dependent CRL4(CRBN) function in myeloma and inform potential mechanisms of drug resistance.

关键词： MULTIPLE myeloma ZINC-finger proteins MONOCLONAL gammopathies CASEIN kinase MYELODYSPLASTIC syndromes

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Custom CRISPR-Cas9 PAM variants via scalable engineering and machine learning

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Nature 2025年 2025 Apr 22页

作者： Rachel A Silverstein Nahye Kim Ann-Sophie Kroell Russell T Walton Justin Delano Rossano M Butcher Martin Pacesa Blaire K Smith Kathleen A Christie Leillani L Ha Ronald J Meis Aaron B Clark Aviv D Spinner Cicera R Lazzarotto Yichao Li Azusa Matsubara Elizabeth O Urbina Gary A Dahl Bruno E Correia Debora S Marks Shengdar Q Tsai Luca Pinello Suk See De Ravin Qin Liu Benjamin P Kleinstiver PhD Program in Biological and Biomedical Sciences Harvard Medical School Boston MA USA. Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. Department of Pathology Massachusetts General Hospital Boston MA USA. Department of Pathology Harvard Medical School Boston MA USA. Institute of Pharmacy and Molecular Biotechnology (IPMB) Faculty of Engineering Sciences Heidelberg University Heidelberg Germany. Department of Biomedical Informatics Harvard Medical School Boston MA USA. Molecular Pathology Unit Massachusetts General Hospital Charlestown MA USA. Krantz Family Center for Cancer Research Massachusetts General Hospital Charlestown Charlestown MA USA. Broad Institute of Harvard and MIT Cambridge MA USA. Ocular Genomics Institute Massachusetts Eye and Ear Boston MA USA. Department of Ophthalmology Harvard Medical School Boston MA USA. Laboratory of Protein Design and Immunoengineering École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics Lausanne Switzerland. CELLSCRIPTTM Madison WI USA. Department of Systems Biology Harvard Medical School Boston MA USA. Department of Hematology St. Jude Children's Research Hospital Memphis TN USA. Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA. Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. bkleinstiver@mgh.harvard.edu. Department of Pathology Massachusetts General Hospital Boston MA USA. bkleinstiver@mgh.harvard.edu. Department of Pathology Harvard Medical School Boston MA USA. bkleinstiver@mgh.harvard.edu.

Engineering and characterizing proteins can be time-consuming and cumbersome, motivating the development of generalist CRISPR-Cas enzymes to enable diverse genome editing applications. However, such enzymes have caveats such as an increased risk of off-target editing. To enable scalable reprogramming of Cas9 enzymes, here we combined high-throughput protein engineering with machine learning (ML) to derive bespoke editors more uniquely suited to specific targets. Via structure/function-informed saturation mutagenesis and bacterial selections, we obtained nearly 1,000 engineered SpCas9 enzymes and characterized their protospacer-adjacent motif (PAM) requirements to train a neural network that relates amino acid sequence to PAM specificity. By utilizing the resulting PAM ML algorithm (PAMmla) to predict the PAMs of 64 million SpCas9 enzymes, we identified efficacious and specific enzymes that outperform evolution-based and engineered SpCas9 enzymes as nucleases and base editors in human cells while reducing off-targets. An in silico directed evolution method enables user-directed Cas9 enzyme design, including for allele-selective targeting of the RHO P23H allele in human cells and mice. Together, PAMmla integrates ML and protein engineering to curate a catalog of SpCas9 enzymes with distinct PAM requirements, and motivates the use of efficient and safe bespoke Cas9 enzymes instead of generalist enzymes for various applications.

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Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 2022年第1期1510卷 79-99页

作者： Cable, Jennifer Weber-Ban, Eilika Clausen, Tim Walters, Kylie J. Sharon, Michal Finley, Daniel J. Gu, Yangnan Hanna, John Feng, Yue Martens, Sascha Simonsen, Anne Hansen, Malene Zhang, Hong Goodwin, Jonathan M. Reggio, Alessio Chang, Chunmei Ge, Liang Schulman, Brenda A. Deshaies, Raymond J. Dikic, Ivan Harper, J. Wade Wertz, Ingrid E. Thoma, Nicolas H. Slabicki, Mikolaj Frydman, Judith Jakob, Ursula David, Della C. Bennett, Eric J. Bertozzi, Carolyn R. Sardana, Richa Eapen, Vinay V. Carra, Serena PhD Sci Writer New York NY 10022 USA Swiss Fed Inst Technol Inst Mol Biol & Biophys Zurich Switzerland Med Univ Vienna Res Inst Mol Pathol IMP Vienna Austria Med Univ Vienna Vienna Bioctr Vienna Austria NCI Ctr Canc Res Struct Biol Ctr Protein Proc SectNIH Frederick MD USA Weizmann Inst Sci Dept Bimolecular Sci Rehovot Israel Harvard Med Sch Dept Cell Biol Boston MA 02115 USA Univ Calif Berkeley Biol & Innovat Genom Inst Dept Plant & Microbial Berkeley CA 94720 USA Harvard Med Sch Dept Pathol Boston MA 02115 USA Brigham & Womens Hosp 75 Francis St Boston MA 02115 USA Univ Hlth Network Princess Margaret Canc Ctr Toronto ON Canada Univ Toronto Dept Med Biophys Toronto ON Canada Univ Vienna Vienna Bioctr VBC Max Perutz Labs Vienna Austria Univ Oslo Inst Basic Med Sci Dept Mol Med Oslo Norway Univ Oslo Ctr Canc Cell Reprogramming Inst Clin Med Oslo Norway Oslo Univ Hosp Inst Canc Res Dept Mol Cell Biol Oslo Norway Sanford Burnham Prebys Med Discovery Inst Program Dev Aging & Regenerat La Jolla CA USA Univ Chinese Acad Scie Inst Biophys Coll Life Sciences CAS Ctr Excellence BiomacromoleculesNatl Lab Bio Beijing Beijing Peoples R China Casma Therapeut Cambridge MA USA Telethon Inst Genet & Med TIGEM Pozzuoli Italy Univ Calif Berkeley Mol & Cell Biol Berkeley CA 94720 USA Tsinghua Univ Peking Univ Joint Ctr Life Sci Sch Life Sci State Key Lab Membrane Biol Beijing Peoples R China Max Planck Inst Biochem Dept Mol Machines & Signaling Martinsried Germany Amgen Inc Thousand Oaks CA USA Goethe Univ Inst Biochem 2 Sch Med Frankfurt Germany Goethe Univ Buchmann Inst Mol Life Sci Frankfurt Germany Harvard Med Sch Blavatn Inst Dept Cell Biol Boston MA 02115 USA Genentech Inc Dept Mol Oncol South San Francisco CA USA Genentech Inc Early Discovery Biochem South San Francisco CA USA Bristol Myers Squibb Brisbane CA USA Friedrich Miescher Inst Biomed Res Basel Switzerland Broad Inst MIT & Harvard Cambridge MA USA Dana Farber C

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.

关键词： aggregation autophagy lysophagy proteasome protein degradation ubiquitin

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Aging and neurodegeneration are associated with increased mutations in single human neurons

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SCIENCE 2018年第6375期359卷 555-558页

作者： Lodato, Michael A. Rodin, Rachel E. Bohrson, Craig L. Coulter, Michael E. Barton, Alison R. Kwon, Minseok Sherman, Maxwell A. Vitzthum, Carl M. Luquette, Lovelace J. Yandava, Chandri N. Yang, Pengwei Chittenden, Thomas W. Hatem, Nicole E. Ryu, Steven C. Woodworth, Mollie B. Park, Peter J. Walsh, Christopher A. Boston Childrens Hosp Manton Ctr Orphan Dis Div Genet & Genom Boston MA 02115 USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Harvard Med Sch Dept Neurol Boston MA 02115 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Program Neurosci Boston MA USA Harvard Med Sch Harvard MIT MD PHD Program Boston MA USA Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA WuXi NextCODE Adv Artificial Intelligence Res Lab Computat Stat & Bioinformat Grp Cambridge MA USA MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA Harvard Med Sch Boston Childrens Hosp Div Genet & Genom Boston MA USA Brigham & Womens Hosp Div Genet 75 Francis St Boston MA 02115 USA Canada Coll Redwood City CA USA

It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons;however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.

关键词： AGING NEURODEGENERATION MUTATION (Biology) NEURONS CYTOSINE deaminase

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Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance

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SCIENCE SIGNALING 2020年第629期13卷 eaau1453页

作者： Temprine, Kelsey Campbell, Nathaniel R. Huang, Richard Langdon, Erin M. Simon-Vermot, Theresa Mehta, Krisha Clapp, Averill Chipman, Mollie White, Richard M. Mem Sloan Kettering Canc Ctr Canc Biol & Genet Program New York NY 10065 USA Mem Sloan Kettering Canc Ctr Gerstner Sloan Kettering Grad Sch Biomed Sci New York NY 10065 USA Weill Cornell Med Coll Triinst MD PhD Program New York NY 10065 USA Univ North Carolina Chapel Hill Chapel Hill NC 27514 USA Weill Cornell Med Coll Dept Med Div Gen Internal Med New York NY 10065 USA Univ Chicago Chicago IL 60637 USA Univ Michigan Ann Arbor MI 48109 USA Broad Inst MIT & Harvard Univ Cambridge MA 02142 USA Columbia Univ Vagelos Coll Phys & Surgeons New York NY 10032 USA

The DNA polymerase Pol kappa plays a key role in translesion synthesis, an error-prone replication mechanism. Pol kappa is overexpressed in various tumor types. Here, we found that melanoma and lung and breast cancer cells experiencing stress from oncogene inhibition up-regulated the expression of Pol kappa and shifted its localization from the cytoplasm to the nucleus. This effect was phenocopied by inhibition of the kinase mTOR, by induction of ER stress, or by glucose deprivation. In unstressed cells, Pol kappa is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Pol kappa increased the abundance of nuclear-localized Pol kappa, particularly in response to the BRAF(V600E)-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAF(V600E) melanoma cells. These observations were analogous to how Escherichia coil encountering cell stress and nutrient deprivation can up-regulate and activate DinB/pol IV, the bacterial ortholog of Pol kappa, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Pol kappa was not excessively mutagenic, indicating that noncatalytic or other functions of Pol kappa could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Pol kappa might prevent drug resistance in some cancer cells.

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Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

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EMBO JOURNAL 2018年第22期37卷 e100294-e100294页

作者： Cox, Andrew G. Tsomides, Allison Yimlamai, Dean Hwang, Katie L. Miesfeld, Joel Galli, Giorgio G. Fowl, Brendan H. Fort, Michael Ma, Kimberly Y. Sullivan, Mark R. Hosios, Aaron M. Snay, Erin Yuan, Min Brown, Kristin K. Lien, Evan C. Chhangawala, Sagar Steinhauser, Matthew L. Asara, John M. Houvras, Yariv Link, Brian Vander Heiden, Matthew G. Camargo, Fernando D. Goessling, Wolfram Harvard Med Sch Brigham & Womens Hosp Boston MA 02115 USA Harvard Med Sch Boston Childrens Hosp Boston MA USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA USA Med Coll Wisconsin Milwaukee WI 53226 USA MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA Harvard Med Sch Beth Israel Deaconess Med Ctr Boston MA USA Weill Cornell Med Coll New York NY USA New York Presbyterian Hosp New York NY USA Harvard Stem Cell Inst Cambridge MA 02138 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Dana Farber Canc Inst Boston MA 02115 USA Harvard MIT Div Hlth Sci & Technol Boston MA 02139 USA Peter MacCallum Canc Ctr Melbourne Vic Australia Univ Melbourne Sir Peter MacCallum Dept Oncol Parkville Vic Australia Univ Melbourne Dept Biochem & Mol Biol Parkville Vic Australia Univ Pittsburgh Childrens Hosp Pittsburgh Med Ctr Pittsburgh PA 15213 USA Novartis Inst BioMed Res Dis Area Oncol Basel Switzerland

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap(-/-) mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap(-/-) mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.

关键词： Hippo pathway Yap glut1 glucose metabolism liver development

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