The splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway.

CCAR1 DNA repair EF hand FANCA Fanconi anemia U2AF1/2 alternative splicing poison exon

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
10 Jul 2024
Historique:
received: 06 09 2023
revised: 15 05 2024
accepted: 25 06 2024
medline: 19 7 2024
pubmed: 19 7 2024
entrez: 18 7 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.molcel.2024.06.031 PMID: 39025073
pubmed: 39025073
pii: S1097-2765(24)00538-0
doi: 10.1016/j.molcel.2024.06.031
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Naoya Harada (N)

Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Shuhei Asada (S)

Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Lige Jiang (L)

Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Huy Nguyen (H)

Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Lisa Moreau (L)

Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Ryan J Marina (RJ)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Karen Adelman (K)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Divya R 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.

Alan D 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.

Classifications MeSH