BRCA1 is an abbreviation for the gene "breast cancer 1, early onset", which encodes a nuclear protein that inhibits tumor development and is a tumor suppressor gene. The BRCA1 gene encodes a nuclear protein. It is a tumor suppressor gene that has the function of maintaining genomic stability. It forms a complex with other tumor suppressors and signal sensors, and plays an important role in gene transcription, DNA damage repair and recombination. This gene has an A/G polymorphism that is associated with susceptibility to diseases such as breast cancer. The cause of breast cancer is closely related to the loss of control of breast epithelial cell proliferation. The BRCA1 (breast cancer gene 1) gene is a tumor suppressor gene that plays a negative role in tumor growth. It plays an important role in DNA damage repair, transcriptional activation and inhibition, and cell cycle regulation. Polymorphisms in this gene can lead to changes in the proliferation of mammary epithelial cells, which in turn affects the susceptibility of breast cancer. Ovarian cancer is a common cancer in women. The BRCA1 gene encodes a nuclear protein, a tumor suppressor gene that functions to maintain genomic stability. It is a complex with other tumor suppressors and signal sensors and plays an important role in gene transcription, DNA damage repair and recombination. Polymorphism of BRCA1 gene affects susceptibility to tumor diseases such as ovarian cancer.
Figure 1. Protein structure of BRCA1.
Structure of the BRCA1 gene
The BRCA1 gene is located on human chromosome 17q21 and consists of 24 exons, including 22 coding exons and 2 non-coding exons. The full length is about 100Kb, and the transcript mRNA is 7.8Kb. The 11th exon is a core exon and encodes more than 60% of the amino acid sequence. This gene has two different promoters, promoter1 and promoter2, which together regulate the transcriptional activity of BRCA1, and the activity of both is kept at a certain proportion, and is mainly based on promoter.
Structure of BRCA1 protein
The BRCA1 protein is a biological macromolecule composed of 1863 amino acids. It has a RING domain at the N-terminus, a BRCT structure with two vertical strings at the C-terminus, and a nuclear localization region (NLS1 and NLS2) at the middle. Nuclear transport, no homology with any other known protein.
DNA damage includes double-stranded damage (DSB) and single-stranded damage (SSB). DSB is one of the most common DNA damages and is the most dangerous in many intracellular genetic damaging. SSB refers to the ribose-phosphate backbone of one strand of the DNA double-stranded structure, due to the tens of thousands of SSBs occurring every day. If not repaired in time, SSBs will produce genetic fragments and even lead to lethal DSBs. After DNA damage, the repair of damaged DNA is mainly through nucleotide excision repair, base excision repair, transcriptional coupling repair, mismatch repair, DNA interstrand cross-linking repair, homologous recombination repair, and non-homologous end repair.
The study found that BRCA1-deficient mouse embryonic hepatocytes could not undergo transcriptional coupling repair, so it can be concluded that BRCA1 may be involved in transcriptional regulation. Two of the BRCA1 are identified as the signal NLS1, NLS2, and the nuclear localization signal BRCA1 is guided into the nucleus to function as a transcriptional regulator. The C-terminal domain of BRCA1 binds to chromatin and DNA structural enzymes, and changes the nucleosome structure by regulating the acetylation and deacetylation of histones, thereby changing the spatial conformation of chromatin and inducing the expression of transcriptional activity of related genes. In cancer, the nucleophilicity of BRCA1 and chromatin-modified proteins is reduced. BRCA1 can regulate the activity of RNA polymerase by RNA helicase, thereby regulating the transcription process, so that the damaged DNA cannot be transcribed, and the transcription factors such as P53 and ATF1 (Figure 2) interact with BRCA1 to regulate the activity of the transcription gene.
Figure 2. Structure of the ATF1 protein.
From the comparative study of DNA repair function, it was found that the repair function has a longer life span (such as cattle), and the short-lived animal repair function is weak. The human repair function is also very strong, but as the age increases, the damage repair function is reduced, which is one of the reasons for the rapid aging of humans after the old age. Studying the relationship between BRCA1 protein structure and function, enhancing the ability of damage repair, and the desire of human longevity is just around the corner.
1. Kass EM.; et al. Jasin M. Double-Strand break repair by homologous recombination in primary Mouse somatic cells requires BRCA1but not the ATM kinase. Proc Natl Acad Sci USA. 2013,110(14):5564～9