BRCA1 and Its Vulnerable C-Terminal BRCT Domain: Structure, Function, Genetic Mutations and Links to Diagnosis and Treatment of Breast and Ovarian Cancer

Abstract

The BRCA1 is a tumor suppressor gene that encodes for the BRCA1 protein, which plays a vital role in DNA repair, cell cycle regulation, and the maintenance of genomic stability. The BRCA1 protein interacts with a variety of other proteins that play essential roles in gene regulation and embryonic development. It is a large protein composed of multiple domains. The C-terminal region of the BRCA1 protein consists of two BRCT domains connected by a short linker. The BRCT domains are crucial in protein–protein interactions as well as in DNA damage response and cell cycle regulation through their phosphoprotein binding modules that recognize the phosphorylated protein sequence motif of other kinases. Mutations within the BRCT domain can disrupt the normal function of BRCA1 and lead to an increased risk of developing breast and ovarian cancer. Herein, we explore the structural characteristics of BRCA1, focusing on the BRCT domain, its interactions with key cellular components, and its involvement in various cellular processes. In addition, the impact of BRCT domain mutations on breast and ovarian cancer susceptibility, prognosis, and treatment options is discussed. By providing a comprehensive understanding of the BRCT domain of BRCA1, this review aims to shed light on the role of this important domain in the pathogenesis and potential therapeutic approaches for breast and ovarian cancer.

Analysis of BRCA1 germline variants (exons 5, 11 and 20) in breast cancer families from Libya

“…Discovering BRCA1/2 variants in an understudied population like Libyans will provide new information on the genetic landscape of hereditary BC in North Africa, improve the understanding of how ethnic diversity impacts variant actionability, and inform the development of more personalized approaches to cancer treatment. The purpose of this study was to investigate the distribution and characteristics of BRCA1 variants in exons 5, 11 and 20 in Libyan families These exons were chosen because they represent hotspots for variants within their respective domains: exon 5 in the RING (Really Interesting New Gene) domain, exon 11 in the region encoded by exons 11–13, and exon 20 in the BRCT ( BRCA1 C-terminal) domain [ 16 , 17 ]. These exons exhibit high rates of clinically significant variations [ 16 ].…”

“…These exons exhibit high rates of clinically significant variations [ 16 ]. Notably, exon 11 encompasses 60% of the coding sequence, making it a particularly relevant target for variant analysis [ 17 ].…”