Evolution of the triplet BRCT domain

• Published in: DNA repair 2023-09, Vol.129, p.103532-103532, Article 103532
• Main Authors: Mota, M.B.S., Woods, N.T., Carvalho, M.A., Monteiro, A.N.A., Mesquita, R.D.
• Format: Article
• Language: English
• Subjects: BRCT; DNA damage response; Domain evolution; ECT2; TOPBP1; Triplet BRCT
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2023.103532

Organisms have evolved a complex system, called the DNA damage response (DDR), which maintains genome integrity. The DDR is responsible for identifying and repairing a variety of lesions and alterations in DNA. DDR proteins coordinate DNA damage detection, cell cycle arrest, and repair, with many of these events regulated by protein phosphorylation. In the human proteome, 23 proteins contain the BRCT (BRCA1 C‐Terminus domain) domain, a modular signaling domain that can bind phosphopeptides and mediate protein-protein interactions. BRCTs can be found as functional single units, tandem (tBRCT), triplet (tpBRCT), and quartet. Here we examine the evolution of the tpBRCT architecture present in TOPBP1 (DNA topoisomerase II binding protein 1) and ECT2 (epithelial cell transforming 2), and their respective interaction partners RAD9 (Cell cycle checkpoint control protein RAD9) and CYK-4 (Rac GTPase-activating protein 1), with a focus on the conservation of the phosphopeptide-binding residues. The pair TOPBP1-RAD9 arose with the Eukaryotes and ECT2-CYK-4 with the Eumetazoans. Triplet structural and functional characteristics were conserved in almost all organisms. The first unit of the triplet (BRCT0) is different from the other two BRCTs but conserved between orthologs for both TOPBP1 and ECT2. BRCT domain evolution simulations suggest a trend to retain the singlet or towards two or three BRCT copies per protein consistent with functional tBRCT and tpBRCT architectures. Our results shed light on the emergence of the function and architecture of multiple BRCT domain organizations and provide information about the evolution of the BRCT triplet. Knowledge of BRCT domain evolution can improve the understanding of DNA damage response mechanisms and signal transduction in DDR. •The TOPBP1-RAD9 interaction pair arose with Eukaryotes.•The ECT2-CYK-4 interaction pair arose with Eumetazoans.•The tpBRCT0 is different from the other two but conserved for TOPBP1 and ECT2 orthologs.•The ECT2 tpBRCT seems to originate from TOPBP1.•The BRCT evolution simulation directed to proteins with few BRCTs.