The protein TIPIN belongs to the CSM3 family. It plays a crucial role in the progression of the S-phase during cell division and is vital for cell survival when DNA damage or replication stress occurs. TIPIN is particularly important for the ATR-CHEK1 pathway, which is part of the replication checkpoint activated by ultraviolet light.
The TIMELESS protein was initially identified as a mammalian homologue of the Drosophila circadian clock protein TIM. It was later discovered to be a core component of the replisome, a large protein assembly responsible for DNA replication . The crystal structure of the N-terminal domain of human TIMELESS, spanning amino acids 1–463, revealed a partial binding site for TIPIN .
The TIMELESS-TIPIN complex is essential for maintaining the integrity of the replication fork during DNA synthesis. It helps in stabilizing the replication fork and preventing its collapse under stress conditions . This complex is also involved in the DNA damage checkpoint during the S-phase, ensuring that any damage is repaired before the cell cycle progresses .
The TIMELESS-TIPIN complex plays a vital role in preserving genomic integrity. It is recruited to replication origin regions and dissociates as replication proceeds. Depletion of this complex can lead to chromosome fragmentation and defects in damage repair, highlighting its importance in maintaining replication fork stability . Additionally, the complex is required for sister chromatid cohesion, which is crucial for accurate chromosome segregation during cell division .