lunes, 8 de octubre de 2018

BRCA1 Interactions

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

The BRCA1 gene is located on the long arm of chromosome 17, at position 17q21. The gene spans around 100 kilobases and codes for a protein containing 1863 amino acids. Mutations or alterations that affect the BRCA1 gene are linked to familial breast and ovarian cancer syndromes. Nearly 10% of all ovarian cancers are caused by mutations in either the BRCA1 or BRCA2 gene and nearly 45% of breast cancers may be caused by mutations in the BRCA1 gene.

Breast cancer is one of the most common cancers and affects as many as 1 in every 9 women in Western countries. The BRCA1 and BRCA2 genes code for tumor suppressor proteins. Mutations in these genes can result in abnormal versions of the proteins that fail to prevent the growth and proliferation of cancer cells.

The BRCA1 gene was mapped in 1990 and cloned in 1994 and the BRCA2 gene was isolated one year later. These proteins mainly maintain genomic integrity through DNA repair and the regulation of transcription processes. Studies have shown that BRCA1 plays important roles in several cellular pathways and loss of proper BRCA1 function can lead to the following:

Defective DNA damage repair
Altered or damaged cellular apoptosis (programmed cell death)
Genetic instability
Tumorigenesis
Centrosome duplication

These wide ranging consequences of the loss of BRCA1 function are explained by the proteins numerous interactions with several molecules, including the products of tumor suppressor genes and cancer-causing genes or oncogenes.

The BRCA1 tumor suppressor interacts with:

DNA damage-repair proteins
Ubiquitin hydrolases
Transcriptional activators and inhibitors
Cell cycle regulators

Proteins that interact with BRCA1 are termed BRCA1-interacting proteins (BIPs). The N-terminal end of BRCA1 contains a zinc-finger domain that can interact with DNA directly or indirectly. The first 109 amino acids of BRCA1 contain a protease-resistant domain that interacts with E2F1 and BAP1. In addition, exon 11 of BRCA1 possesses two nuclear-localization signals for targeting BRCA1 to the nucleus. This exon interacts with the RAD50, RAD51, RB and c-Myc.

The C-terminal end of BRCA1 interacts directly or indirectly with p53, RNA Polymerase II, RNA helicaseA, p300 and CBP (CREB binding protein), BRCA2, histone-deacetylase complex, RB and CtIP.

BRCA1 in the regulation of transcription

BRCA1 regulates transcription by modifying gene expression in response to cellular stress and DNA damage. Studies have shown that the C-terminus of BRCA1 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.

The C-terminus of BRCA1 contains two domains that interact with multiple transcription activators and repressors. The C-terminus binds to the GAL4 DNA-binding domain and is transfected into cells, which activates the transcription of GAL4-dependent promoters. This region also interacts with p53 and stimulates p53-dependent transcription of the p21 promoter. Furthermore, the C-terminus of BRCA1 interacts with the RNA polymerase II holoenzyme to act as transcriptional activator.

BRCA1 and the cell cycle regulation

BRCA1 interacts with several proteins that regulate the cell cycle. These include E2F, CDC2 and cyclins. The maximum control is seen in late G1 phase to S phase.