DNA replication checkpoint
Accurate replication of the millions or billions of DNA base pairs in a eukaryotic genome is a remarkable achievement. This accomplishment is even more astonishing when one considers for DNA synthesis are rarely ideal. Damaged template, protein complexes bound to DNA, and poor supply of dNTPs are among the many obstacles that must be overcome to replicate genome. All of these situations can stall replication forks.
Stalled forks pose grave threats to genome integrity because they can rearrange, break, or collapse through disassembly of the replication complex. The pathways that respond to replication stress are signal transduction pathways that are conserved across evolution.
Atop the pathways are also ATM/ATR family kinases. These kinases together with a trimeric checkpoint clamp (termed 9-1-1 complex) and five-subunit checkpoint clamp loader (Rad17-RFC2-RFC3-RFC4-RFC5) senses stalled replication forks and transmit a checkpoint signal.
One of major functions of replication checkpoint is to prevent the onset of mitosis by regulating mitotic control proteins such as Cdc25. But perhaps the most important activity of replication checkpoint is to stabilize and protect replication forks.
The protein kinase Cds1 (human Chk2 homolog; in human, Chk1 is a functional Cds1 homolog) is a critical effector of the replication checkpoint in the fission yeast Schizosaccharomyces pombe.
Cds1 is required to prevent stabilization of replication fork in cells treated with hydroxyurea (HU), a ribonucleotide reductase inhibitor that stalls replication by depleting dNTPs. In the budding yeast Saccharomyces cerevisiae, a failure to activate Rad53 (Chk2 homolog) is associated with collapse and regression of replication forks and gross chromosomal rearrangements in cells treated with HU.
See also
replication fork protection complex (FPC)