RB·E2F1 complex mediates DNA damage responses through transcriptional regulation of ZBRK1.
J Biol Chem
; 285(43): 33134-33143, 2010 Oct 22.
Article
en En
| MEDLINE
| ID: mdl-20713352
ABSTRACT
RB plays an essential role in DNA damage-induced growth arrest and regulates the expression of several factors essential for DNA repair machinery. However, how RB coordinates DNA damage response through transcriptional regulation of genes involved in growth arrest remains largely unexplored. We examined whether RB can mediate the response to DNA damage through modulation of ZBRK1, a zinc finger-containing transcriptional repressor that can modulate the expression of GADD45A, a DNA damage response gene, to induce cell cycle arrest in response to DNA damage. We found that the ZBRK1 promoter contains an authentic E2F-recognition sequence that specifically binds E2F1, but not E2F4 or E2F6, together with chromatin remodeling proteins CtIP and CtBP to form a repression complex that suppresses ZBRK1 transcription. Furthermore, loss of RB-mediated transcriptional repression led to an increase in ZBRK1 transcript levels, correlating with increased sensitivity to ultraviolet (UV) and methyl methanesulfonate-induced DNA damage. Taken together, these results suggest that the RB·CtIP (CtBP interacting protein)/CtBP (C terminus-binding protein) /E2F1 complex plays a critical role in ZBRK1 transcriptional repression, and loss of this repression may contribute to cellular sensitivity of DNA damage, ultimately leading to carcinogenesis.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
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Transcripción Genética
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Daño del ADN
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Proteína de Retinoblastoma
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Elementos de Respuesta
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Complejos Multiproteicos
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Factor de Transcripción E2F1
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2010
Tipo del documento:
Article
País de afiliación:
Taiwán