Evolution of the triplet BRCT domain

Area of Science:

• Molecular Biology
• Evolutionary Biology
• Genetics

Background:

• Organisms utilize the DNA damage response (DDR) to maintain genome integrity.
• Protein phosphorylation is a key regulatory mechanism in DDR pathways.
• The BRCA1 C-Terminus (BRCT) domain is a phosphopeptide-binding module found in 23 human proteins, mediating interactions.

Purpose of the Study:

• To investigate the evolutionary history of the triplet BRCT (tpBRCT) architecture in TOPBP1 and ECT2.
• To analyze the conservation of phosphopeptide-binding residues within tpBRCT domains and their partners RAD9 and CYK-4.
• To understand the emergence of multiple BRCT domain organizations and their role in DDR.

Main Methods:

• Comparative analysis of tpBRCT domain evolution in TOPBP1 and ECT2.
• Examination of conserved phosphopeptide-binding residues in RAD9 and CYK-4 interaction partners.
• BRCT domain evolution simulations to predict trends in domain copy number.

Main Results:

• The TOPBP1-RAD9 pair emerged with Eukaryotes, while ECT2-CYK-4 emerged with Eumetazoans.
• Triplet BRCT structural and functional characteristics are highly conserved across organisms.
• The initial BRCT unit (BRCT0) is distinct but conserved in TOPBP1 and ECT2 orthologs.

Conclusions:

• BRCT domain evolution favors retention of singlet or two-to-three copy arrangements, supporting tBRCT and tpBRCT architectures.
• Understanding BRCT domain evolution provides insights into DDR mechanisms and signal transduction.
• The study elucidates the functional and architectural evolution of multi-BRCT domain proteins.