lunes, 8 de octubre de 2018

BRCA1 Gene Transcription

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By Ananya Mandal, MDReviewed by Sally Robertson, B.Sc.

The BRCA1 gene is a sequence located on the long arm of chromosome 17, at position 17q21. The gene spans around 100 kilobases and codes for a tumor suppressor protein containing 1863 amino acids. This protein combines with other tumor suppressors and DNA repair sensors to form a large protein complex called the BRCA1-associated genome surveillance complex (BASC). Mutations or alterations that affect the BRCA1 gene are linked to familial breast and ovarian cancer syndromes.

BRCA1 and the transcription process

The BRCA1 protein regulates transcription by modifying gene expression in response to cellular stress and DNA damage. Studies have shown that the C-terminus of BRCA1 in humans which incorporates amino acids 1528 to 1863 forms a complex with RNA polymerase II, an enzyme that makes mRNA precursors as well as many noncoding RNAs.

Many transcription factors bind to the internal portion of BRCA1, which may be involved in transporting signals to RNA polymerase II. Microarray studies have shown that cell cycle progression inhibitors and stress response factors are activated by the over expression of BRCA1. Furthermore, research has demonstrated that BRCA1 acts as a co-stimulator of the tumor suppressor p53 as well as interacting with it. p53 is also stabilized by the over expression of BRCA1, indicating that BRCA1 serves to stimulate p53 pathways.

BRCA1 also interacts with a transcription factor that binds to a specific DNA sequence or motif located in the promoter region of many BRCA1 transcriptional targets such as p21, GADD45 and EGR1. Studies have shown that BRCA1 interacts with STAT1, binding to its transcriptional activation domain in order to regulate p21, a protein involved in cell cycle arrest. This interaction between BRCA1 and STAT1 was shown to be important in the arrest of cell growth after treatment with IFN-γ, due to the induction of p21 which has an IFN γ-responsive element in its promoter.

These findings suggest that BRCA1 brings about cellular responses such as cell cycle arrest and apoptosis and that it achieves this by acting as a bridging protein that connects DNA damage and stress response pathways.