MTHFD1与BRD4的相互作用将叶酸代谢与转录调控联系起来。,Nature Genetics

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MTHFD1与BRD4的相互作用将叶酸代谢与转录调控联系起来。
Nature Genetics ( IF 31.7 ) Pub Date : 2019-05-27 , DOI: 10.1038/s41588-019-0413-z
Sara Sdelci _{1,

2} , André F Rendeiro ₁ , Philipp Rathert _{3,

4} , Wanhui You _{1,

5} , Jung-Ming G Lin ₁ , Anna Ringler _{1,

5} , Gerald Hofstätter _{1,

5} , Herwig P Moll ₆ , Bettina Gürtl ₁ , Matthias Farlik ₁ , Sandra Schick _{1,

5} , Freya Klepsch ₁ , Matthew Oldach ₁ , Pisanu Buphamalai ₁ , Fiorella Schischlik ₁ , Peter Májek ₁ , Katja Parapatics ₁ , Christian Schmidl _{1,

7} , Michael Schuster ₁ , Thomas Penz ₁ , Dennis L Buckley ₈ , Otto Hudecz ₉ , Richard Imre ₉ , Shuang-Yan Wang _{10,

11} , Hans Michael Maric _{10,

11} , Robert Kralovics _{1,

12} , Keiryn L Bennett ₁ , Andre C Müller ₁ , Karl Mechtler ₃ , Jörg Menche ₁ , James E Bradner ₈ , Georg E Winter ₁ , Kristaps Klavins ₁ , Emilio Casanova _{6,

13} , Christoph Bock _{1,

12,

14} , Johannes Zuber _{3,

15} , Stefan Kubicek _{1,

6}

Affiliation

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
Biochemistry Department, University Stuttgart, Stuttgart, Germany.
Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Regensburg Center for Interventional Immunology (RCI), University Regensburg and University Medical Center, Regensburg, Germany.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany.
Institute of Structural Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Max Planck Institute for Informatics, Saarbrücken, Germany.
Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.

含组蛋白乙酰基阅读器含溴结构域的蛋白质4（BRD4）是染色质结构和转录的重要调节剂，但调节其活性的因素仍然难以捉摸。在这里，我们描述了BRD4的遗传和物理相互作用子的两个互补筛选，它们会聚在叶酸途径酶MTHFD1（亚甲基四氢叶酸脱氢酶，环水解酶和甲酰基四氢叶酸合成酶1）上。我们显示，一部分MTHFD1驻留在细胞核中，通过与BRD4的直接相互作用而被募集到不同的基因组位点。抑制BRD4或MTHFD1会导致核代谢产物组成和基因表达发生类似变化。这两种途径的药理学抑制剂在体外和体内协同作用以损害癌细胞的生存能力。

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更新日期：2019-05-27

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