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Regulación de las enzimas. IRBIT es un nuevo regulador de la ribonucleótido reductasa en eucariotas superiores

Alexei Arnaoutov¹, Mary Dasso²

¹Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. arnaouta@mail.nih.gov.

Science (New York, N.Y.)

|September 20, 2014

Resumen

La proteína IRBIT inhibe la replicación del ADN al formar un complejo con la ribonucleótido reductasa (RNR), lo que mejora la inhibición del trifosfato de desoxiaadenosina (dATP). Esta interacción IRBIT-RNR impacta la progresión del ciclo celular en las células humanas.

Área de la Ciencia:

Biología Molecular Biología Molecular
Biología celular Biología celular.
La bioquímica es la bioquímica.

Sus antecedentes:

La ribonucleotide reductasa (RNR) es esencial para la replicación del ADN y la estabilidad genómica, manteniendo piscinas equilibradas de deoxinucleotide trifosfato (dNTP).
El RNR eucariótico está regulado por mecanismos alostéricos y, en la levadura, por pequeños inhibidores de proteínas como Sml1p y Spd1p.

Objetivo del estudio:

Investigar el papel de la proteína metazoal IRBIT en la regulación de la RNR en los eucariotas superiores.
Aclarar el mecanismo por el cual el IRBIT interactúa y modula la actividad RNR.

Principales métodos:

Se analizó la formación de un complejo dependiente del trifosfato de deoxyadenosina (dATP) entre IRBIT y RNR.
La fosforilación IRBIT fue estudiada como un mecanismo regulador para la formación de complejos.
El impacto de la ablación IRBIT en los grupos de dNTP y la progresión del ciclo celular se evaluó en células HeLa.

Principales resultados:

IRBIT forma un complejo dependiente de dATP con RNR, estabilizando dATP en el sitio activo de la enzima e inhibiendo RNR.
La fosforilación de IRBIT regula la formación del complejo RNR-IRBIT.
La ablación de IRBIT en las células HeLa conduce a piscinas de dNTP desequilibradas y a una progresión alterada del ciclo celular.

Conclusiones:

IRBIT actúa como un nuevo regulador de RNR en metazoos, mejorando la inhibición alosterica mediada por dATP.
La interacción IRBIT-RNR proporciona una nueva capa de control sobre los grupos dNTP cruciales para el metabolismo del ADN y la fidelidad del ciclo celular.

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