The fanconi anemia core complex acts as a transcriptional co-regulator in hairy enhancer of split 1 signaling.
Mutations in one of the 13 Fanconi anemia (FA) genes cause a progressive bone marrow failure disorder associated with developmental abnormalities and a predisposition to cancer. Although FA has been defined as a DNA repair disease based on the hypersensitivity of patient cells to DNA cross-linking agents, FA patients develop various developmental defects such as skeletal abnormalities, microphthalmia, and endocrine abnormalities that may be linked to transcriptional defects. Recently, we reported that the FA core complex interacts with the transcriptional repressor Hairy Enhancer of Split 1 (HES1) suggesting that the core complex plays a role in transcription. Here we show that the FA core complex contributes to transcriptional regulation of HES1-responsive genes, including HES1 and the cyclin-dependent kinase inhibitor p21(cip1/waf1). Chromatin immunoprecipitation studies show that the FA core complex interacts with the HES1 promoter but not the p21(cip1/waf1) promoter. Furthermore, we show that the FA core complex interferes with HES1 binding to the co-repressor transducin-like-Enhancer of Split, suggesting that the core complex affects transcription both directly and indirectly. Taken together these data suggest a novel function of the FA core complex in transcriptional regulation.
Tremblay
Cédric S
CS
Centre Hospitalier de l'Université Laval, Université Laval, Québec GIV 4G2, Canada.
Huard
Caroline C
CC
Centre Hospitalier de l'Université Laval, Université Laval, Québec GIV 4G2, Canada.
Huang
Feng-Fei
FF
Centre Hospitalier de l'Université Laval, Université Laval, Québec GIV 4G2, Canada.
Habi
Ouassila
O
Centre Hospitalier de l'Université Laval, Université Laval, Québec GIV 4G2, Canada.
Bourdages
Valérie
V
Centre Hospitalier de l'Université Laval, Université Laval, Québec GIV 4G2, Canada.
Lévesque
Georges
G
Centre Hospitalier de l'Université Laval, Université Laval, Québec GIV 4G2, Canada; Medical Biology and Université Laval, Québec GIV 4G2, Canada.
Carreau
Madeleine
M
Medical Biology and Université Laval, Québec GIV 4G2, Canada; Departments of Pediatrics Université Laval, Québec GIV 4G2, Canada. Electronic address: Madeleine.Carreau@crchul.ulaval.ca.