BRCT Domains: Structure, Functions, and Implications in Disease—New Therapeutic Targets for Innovative Drug Discovery against Infections

Abstract

The search for new therapeutic targets and their implications in drug development remains an emerging scientific topic. BRCT-bearing proteins are found in Archaea, Bacteria, Eukarya, and viruses. They are traditionally involved in DNA repair, recombination, and cell cycle control. To carry out these functions, BRCT domains are able to interact with DNA and proteins. Moreover, such domains are also implicated in several pathogenic processes and malignancies including breast, ovarian, and lung cancer. Although these domains exhibit moderately conserved folding, their sequences show very low conservation. Interestingly, sequence variations among species are considered positive traits in the search for suitable therapeutic targets, since non-specific drug interactions might be reduced. These main characteristics of BRCT, as well as its critical implications in key biological processes in the cell, have prompted the study of these domains as therapeutic targets. This review explores the possible roles of BRCT domains as therapeutic targets for drug discovery. We describe their common structural features and relevant interactions and pathways, as well as their implications in pathologic processes. Drugs commonly used to target these domains are also presented. Finally, based on their structures, we describe new drug design possibilities using modern and innovative techniques.

BRCA1 Interaction with Non-Canonical DNA Structures: Insights into Genome Maintenance and Disease Mechanisms

“…Based on these studies, we generated BRCA1 constructs DBD1 (aa340-554) and DBD2 (aa894-1057). The BRCT domain, known to interact with DNA and proteins involved in DNA repair and recombination [49], was also studied using a BRCT construct (aa1646-1863). Previous studies, while informative, used qualitative methods that did not provide exact DNA binding affinities.…”

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

“…Similarly, other residues in the α2 helix interact with those in the β4 sheet. The highly conserved residues are located in the central β sheets (β1, β3, β4) and the α1 and α3 helices, whereas the α2 helix shows the greatest variability within the BRCT protein family [ 15 ]. In addition, the β1, α1, α1–β2 loop, β3, α3, and C-terminal end regions contain five conserved hydrophobic motifs, named A, B, C, D, and E, respectively.…”

“…However, the physiological significance of many such mutations remains unknown due to the lack of BRCT functional assays. Two missense mutations in the BRCT domain were reported in Chinese women with familiar breast cancer, showing similar functions to non-mutated carriers and being associated with reduced growth and stimulated apoptosis [ 15 ]. Previous studies identified six BRCT domain missense mutations (Ser 1655, Val 1696, Arg 1699, Lys 1702, Ala 1708, and Met 1775) that contribute to BRCA1 loss of function and disease through protein-destabilizing effects ( Table 1 ) ( Figure 3 ).…”

“…A typical BRCT domain has 90 to 100 amino acid residues and folds as a globular domain with secondary structural elements arranged as βαββαβα [13]. It has been described as a four-stranded parallel β-sheet (β1, β2, β3, and β4) surrounded by two alpha helices (α1 and α3) located at the C-terminal end, a single α-helix (α2) at the N-terminal end, and two surface loops connecting β1 to α1 and α2 to β3 (the overall structure is β1-α1-β2-β3-α2-β4-α3) (Figure 2) [14,15]. Some hydrophobic interactions occur between certain residues of the α1 helix and those of the β1 and β2 sheets.…”

Unwrap RAP1’s Mystery at Kinetoplastid Telomeres

“…Particularly, functions of T. brucei RAP1 in telomeric silencing and telomere stability maintenance are intimately involved in the regulation of antigenic variation [52,[103][104][105][106][107], an essential pathogenesis mechanism [108], as the major surface antigen VSG is expressed exclusively from subtelomeric loci [109][110][111][112]. All known RAP1 homologs have an N-terminal BRCA1 C-terminus (BRCT) domain that is frequently identified in proteins involved in the DNA damage response or cell cycle checkpoint [113,114], a central Myb domain that typically binds dsDNA [115,116], and a RAP1 C-terminus (RCT) domain that is a protein-protein interaction domain conserved among all RAP1 homologs [31] (Figure 1). Below, I will discuss RAP1's functions in telomeric silencing and chromosome end protection, focusing on the similarities and differences between TbRAP1 and yeast and mammalian RAP1 homologs.…”