دورية أكاديمية
The splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway.
العنوان: | The splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway. |
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المؤلفون: | Harada N; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Asada S; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Jiang L; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Nguyen H; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Moreau L; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Marina RJ; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Adelman K; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Iyer DR; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: divyar_iyer@dfci.harvard.edu., D'Andrea AD; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu. |
المصدر: | Molecular cell [Mol Cell] 2024 Jul 25; Vol. 84 (14), pp. 2618-2633.e10. Date of Electronic Publication: 2024 Jul 17. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Cambridge Ma : Cell Press Original Publication: Cambridge, Mass. : Cell Press, c1997- |
مواضيع طبية MeSH: | Fanconi Anemia*/genetics , Fanconi Anemia*/metabolism , Fanconi Anemia Complementation Group A Protein*/genetics , Fanconi Anemia Complementation Group A Protein*/metabolism , RNA Splicing* , Splicing Factor U2AF*/metabolism , Splicing Factor U2AF*/genetics , Cell Cycle Proteins*/genetics , Cell Cycle Proteins*/metabolism , Apoptosis Regulatory Proteins*/genetics , Apoptosis Regulatory Proteins*/metabolism, Humans ; BRCA1 Protein/metabolism ; BRCA1 Protein/genetics ; BRCA2 Protein/metabolism ; BRCA2 Protein/genetics ; DNA Repair ; Endodeoxyribonucleases ; Exons ; HEK293 Cells ; HeLa Cells ; Protein Binding ; RNA Precursors/metabolism ; RNA Precursors/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction ; Spliceosomes/metabolism ; Spliceosomes/genetics |
مستخلص: | The twenty-three Fanconi anemia (FA) proteins cooperate in the FA/BRCA pathway to repair DNA interstrand cross-links (ICLs). The cell division cycle and apoptosis regulator 1 (CCAR1) protein is also a regulator of ICL repair, though its possible function in the FA/BRCA pathway remains unknown. Here, we demonstrate that CCAR1 plays a unique upstream role in the FA/BRCA pathway and is required for FANCA protein expression in human cells. Interestingly, CCAR1 co-immunoprecipitates with FANCA pre-mRNA and is required for FANCA mRNA processing. Loss of CCAR1 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA protein expression. A unique domain of CCAR1, the EF hand domain, is required for interaction with the U2AF heterodimer of the spliceosome and for excision of the poison exon. Taken together, CCAR1 is a splicing modulator required for normal splicing of the FANCA mRNA and other mRNAs involved in various cellular pathways. Competing Interests: Declaration of interests A.D.D. reports consulting for AbbVie, Deerfield Management Company, Impact Therapeutics, Moderna Therapeutics, PrimeFour Therapeutics, Schrödinger Inc., Servier BioInnovation LLC, and Tango Therapeutics; is a Scientific Advisory Board Member and Stockholder for Impact Therapeutics and Covant Therapeutics. K.A. is a member of the Advisory Board of Molecular Cell, the SAB of CAMP4 Therapeutics, consults for Syros Pharmaceuticals and Odyssey Therapeutics, and received research funding from Novartis not related to this work. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
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معلومات مُعتمدة: | P30 CA006516 United States CA NCI NIH HHS; R01 HL052725 United States HL NHLBI NIH HHS |
فهرسة مساهمة: | Keywords: CCAR1; DNA repair; EF hand; FANCA; Fanconi anemia; U2AF1/2; alternative splicing; poison exon |
المشرفين على المادة: | 0 (BRCA1 Protein) 0 (BRCA1 protein, human) 0 (BRCA2 Protein) 0 (BRCA2 protein, human) EC 3.1.- (Endodeoxyribonucleases) 0 (FANCA protein, human) 0 (Fanconi Anemia Complementation Group A Protein) EC 3.1.- (RBBP8 protein, human) 0 (RNA Precursors) 0 (RNA, Messenger) 0 (Splicing Factor U2AF) 0 (U2AF1 protein, human) 0 (CCAR1 protein, human) 0 (Cell Cycle Proteins) 0 (Apoptosis Regulatory Proteins) |
تواريخ الأحداث: | Date Created: 20240718 Date Completed: 20240728 Latest Revision: 20240815 |
رمز التحديث: | 20240815 |
مُعرف محوري في PubMed: | PMC11321822 |
DOI: | 10.1016/j.molcel.2024.06.031 |
PMID: | 39025073 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1097-4164 |
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DOI: | 10.1016/j.molcel.2024.06.031 |