RAD9A
Cells activate checkpoint pathways in response to DNA damage or a block to replication, that prevent cell cycle progression by inhibiting the basic cell cycle machinery until the problem is fixed.
Various forms of DNA damage and various treatments that block replication trigger these checkpoints. Recent work on the mechanisms of DNA damage and replication cell cycle checkpoints has revealed great similarity between the checkpoint pathways of organisms as diverse as yeasts, flies, humans and mouse.
However, there are differences in the ways these organisms regulate their cell cycles. In fission yeast, checkpoint responds to DNA damage induced by IR (Ionizing Radiation) and UV light, as well as to DNA replication inhibitors.
In humans and mouse, Chk (Checkpoint Kinase) is phosphorylated and activated by ATR (ATM and Rad3-related protein kinase), and the ATR/Chk1 pathway responds to agents that impair DNA replication, either directly (hydroxyurea, aphidicolin) or indirectly (UV irradiation).
In response to DNA damage, the Rad9-Hus1-Rad1 complex in fission yeast (Ddc1-Mec3-Rad17 in budding yeast) is loaded by Rad17 (Rad24 in budding yeast), which is itself constitutively DNA associated along with the RFC2-5 (Replication Factor-C) complex.
The phosphoinositide kinase family of Chk components, including the yeast Rad3 in Schizosaccharomyces pombe (Fission yeast), Mec1/Tel1 in Saccharomyces cerevisiae (Budding yeast), mammalian (Homo sapiens and Mus musculus) ATM (Ataxia Telangiectasia-Mutated), ATR (ATM/Rad3-related) and Mei41 in Drosophila regulate the activities of two downstream effectors serine/threonine kinases, Cds1 and Chk1 (called Grapes (Grp) in Drosophila) that are evolutionarily conserved.
The Cds1 family includes conserved representatives from yeasts (Cds1 in fission yeast and Rad53 in budding yeast) to man (hCds1/Chk2). In S. pombe, Chk1 and Mik is the effector of the G2/M DNA damage checkpoint pathway and is downstream of the Rad3 kinase, whereas in S. cerevisiae, Chk1 is downstream of Mec1.
One of the best defined and well characterized targets of Chk1 is CDC25, the dual specificity tyrosine/threonine phosphatase that dephosphorylates the mitotic inducer CDC2, resulting in CDC2 serine/threonine kinase activity that drives mitosis. Cds1 is the effector of the replication checkpoint pathway and is required for cells to survive treatments that block replication, such as hydroxyurea.
The Chk1 and Chk2 serine/threonine kinases also play important roles in cell cycle checkpoint signaling pathways in higher organisms.
In Drosophila, Chk1 functions not only in a checkpoint triggered by UV-damaged DNA but also in an S-phase checkpoint triggered by a replication blockade and loss of Chk2 results in ionizing radiation sensitivity, resistance to ionizing radiation-induced apoptosis, and genetic instability.
See also
RAD9s