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TGFß pathway is required for viable gestation of Fanconi anemia embryos.
Rodríguez, Alfredo; Epperly, Michael; Filiatrault, Jessica; Velázquez, Martha; Yang, Chunyu; McQueen, Kelsey; Sambel, Larissa A; Nguyen, Huy; Iyer, Divya Ramalingam; Juárez, Ulises; Ayala-Zambrano, Cecilia; Martignetti, David B; Frías, Sara; Fisher, Renee; Parmar, Kalindi; Greenberger, Joel S; D'Andrea, Alan D.
Afiliación
  • Rodríguez A; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Epperly M; Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, México, México.
  • Filiatrault J; Instituto Nacional de Pediatría, Mexico City, Mexico.
  • Velázquez M; University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
  • Yang C; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • McQueen K; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Sambel LA; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Nguyen H; Center for DNA Damage and DNA Repair, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Iyer DR; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Juárez U; Center for DNA Damage and DNA Repair, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Ayala-Zambrano C; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Martignetti DB; Center for DNA Damage and DNA Repair, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Frías S; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Fisher R; Center for DNA Damage and DNA Repair, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Parmar K; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • Greenberger JS; Instituto Nacional de Pediatría, Mexico City, Mexico.
  • D'Andrea AD; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
PLoS Genet ; 18(11): e1010459, 2022 11.
Article en En | MEDLINE | ID: mdl-36441774
Overexpression of the TGFß pathway impairs the proliferation of the hematopoietic stem and progenitor cells (HSPCs) pool in Fanconi anemia (FA). TGFß promotes the expression of NHEJ genes, known to function in a low-fidelity DNA repair pathway, and pharmacological inhibition of TGFß signaling rescues FA HSPCs. Here, we demonstrate that genetic disruption of Smad3, a transducer of the canonical TGFß pathway, modifies the phenotype of FA mouse models deficient for Fancd2. We observed that the TGFß and NHEJ pathway genes are overexpressed during the embryogenesis of Fancd2-/- mice and that the Fancd2-/-Smad3-/- double knockout (DKO) mice undergo high levels of embryonic lethality due to loss of the TGFß-NHEJ axis. Fancd2-deficient embryos acquire extensive genomic instability during gestation which is not reversed by Smad3 inactivation. Strikingly, the few DKO survivors have activated the non-canonical TGFß-ERK pathway, ensuring expression of NHEJ genes during embryogenesis and improved survival. Activation of the TGFß-NHEJ axis was critical for the survival of the few Fancd2-/-Smad3-/- DKO newborn mice but had detrimental consequences for these surviving mice, such as enhanced genomic instability and ineffective hematopoiesis.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anemia de Fanconi Límite: Animals Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anemia de Fanconi Límite: Animals Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos