replication fork protection complex
The DNA replication checkpoint stabilizes replication forks that have stalled at DNA adducts and other lesions that block DNA polymerases.
In the absence of DNA replication checkpoint, stalled forks are thought to collapse, creating strand break that threatens genome stability and cell viability.
Therefore, discovering how cells cope with aberrant replication forks is essential for understanding mechanisms of genome maintenance.
The Chk1 and Chk2/Cds1 checkpoint kinases, which are key mediators of DNA damage and DNA replication checkpoints, are thought to be involved in cancer development.
The Swi1 protein is required for survival of replication fork arrest and effective activation of Chk2 kinase in fission yeast. Swi1 forms tight complex with Swi3 protein and moves with replication forks.
Swi1-Swi3 complex is also important for proficient DNA replication even in the absence of agents that cause genotoxic stress, creating single-strand DNA gaps at replication forks.
These results led to propose Swi1-Swi3 define a replication fork protection complex (FPC) that stabilizes replication forks in a configuration that is recognized by replication checkpoint sensors.
Interestingly, Tof1 protein (Budding yeast Swi1 homolog) has been reported to have similar functions. Tof1 is also involved in Rad53 (Chk2 homolog) activation and travels with replication fork.
Tof1 is needed to restrain fork progression when DNA synthesis is inhibited by HU indicating that Tof1 is required for coordination of DNA synthesis and replisome (replication machinery) movement.
FPC may be conserved across evolution
Swi1 and Tof1 belong to a large protein family that was first defined by metazoan Tim1 (hTIMELESS). Drosophila melanogaster and mammalian Tim1s are implicated in circadian rhythmic oscillation, whereas the Caenorhabditis elegans Tim1 is required for proper chromosome cohesion and segregation.
All species listed above have Swi3 homolgs in their genomes suggesting that Swi1-Swi3 complex may be conserved amongst eukaryotes. It will be interesting to determine whether these conserved complexes are involved in DNA replication and maintenance of genome integrity.