CTIP

CtIP, encoded by the RBBP8 gene, is a nuclear protein that participates in the DNA damage response, particularly the repair of DNA double-strand breaks by homologous recombination. It functions as a cofactor of the MRN complex and BRCA1, promoting the initial processing of DNA ends necessary for accurate repair.

Mechanism: After a double-strand break, CtIP is recruited to the break site by the MRN complex and BRCA1. It stimulates DNA end resection by enhancing the nuclease activity of MRE11 and facilitating the generation of 3' single-stranded DNA overhangs. This resection enables binding by RPA and subsequent replacement by RAD51, directing repair by homologous recombination. CtIP activity is coordinated with the cell cycle, being most active in S and G2 phases when HR is favored.

Regulation: CtIP function is controlled by phosphorylation in response to DNA damage and cell cycle cues. ATM/ATR-mediated phosphorylation and cyclin-dependent kinase (CDK)–dependent phosphorylation modulate its interactions and activity, influencing recruitment to DNA breaks and its ability to promote resection. Protein interactions and post-translational modifications help ensure proper timing and level of activity.

Structure and interactions: The protein contains an N-terminal region implicated in self-association and interaction with the MRN complex, and a C-terminal region that participates in BRCA1 engagement and regulatory phosphorylation. Multiple phosphorylation sites modulate stability and function, contributing to precise control of end resection.

Clinical significance: Because of its central role in homologous recombination, CtIP deficiency or dysregulation can lead to genomic instability and increased sensitivity to DNA-damaging agents. Alterations in CtIP have been observed in various cancers, making it a subject of interest for understanding genome maintenance and potential therapeutic targeting in DNA damage response pathways.