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Mecanismos de la mutagénesis de APOBEC3 en las células cancerosas humanas

  • 0Broad Institute of MIT and Harvard, Cambridge, MA, USA. mpetljak@broadinstitute.org.
Nature +

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21 de julio de 2022

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21 de julio de 2022

Ver abstracta en PubMed

Resumen

Este resumen es generado por máquina.

Las enzimas endógenas APOBEC3 impulsan las mutaciones del cáncer. La eliminación de APOBEC3A redujo las firmas, mientras que la eliminación de APOBEC3B aumentó la actividad de APOBEC3A, revelando mecanismos clave de mutagénesis.

Área De La Ciencia

  • La genética
  • Biología molecular
  • Investigación del cáncer

Sus Antecedentes

  • La familia APOBEC3 (enzima de edición de ARNm de la apolipoproteína B, parecida a un polipéptido catalítico 3) de las desaminasas de citosina está relacionada con las firmas mutacionales comunes del cáncer.
  • Los mecanismos de la mutagénesis de APOBEC3 y su papel causal en los genomas del cáncer humano siguen siendo poco conocidos.

Objetivo Del Estudio

  • Investigar los mecanismos de mutagénesis de APOBEC3 en líneas celulares de cáncer humano.
  • Establecer un vínculo causal directo entre las enzimas APOBEC3 endógenas y las firmas mutacionales del cáncer.

Principales Métodos

  • Deleción de genes de APOBEC3A y APOBEC3B en líneas celulares de cáncer humano.
  • Análisis de secuenciación de todo el genoma de 251 clones de líneas celulares de cáncer (mama, vejiga, linfoma).
  • Evaluación de las funciones de UNG y REV1 en la mutagénesis mediada por APOBEC3.

Principales Resultados

  • La eliminación de APOBEC3A disminuyó significativamente las firmas mutacionales asociadas con APOBEC3.
  • La eliminación combinada de APOBEC3A y APOBEC3B redujo las cargas de mutación, pero no las eliminó.
  • La deleción de APOBEC3B aumentó los niveles, la actividad y la mutagenesis de la proteína APOBEC3A.

Conclusiones

  • Las deaminasas APOBEC3 endógenas generan directamente firmas mutacionales prevalentes en las células cancerosas humanas.
  • APOBEC3A se identifica como el conductor principal de estas mutaciones.
  • APOBEC3B puede modular la actividad de APOBEC3A y contribuye con sus propias mutaciones; UNG y REV1 desempeñan funciones en tipos específicos de mutación.

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