InterPro domain: IPR007268

This entry represents the DNA damage checkpoint protein Rad9 and its homologue in budding yeast, Ddc1. Rad9 forms a complex with Hus1 and Rad1 (called 9-1-1 complex). Ddc1 forms a similar complex with Mec1 and Rad17. Structurally, the 9-1-1 / Ddc1-Mec3-Rad17 complex is similar to the PCNA complex, which forms trimeric ring-shaped clamps. The 9-1-1 / Ddc1-Mec3-Rad17 complex plays a role in checkpoint activation that permits DNA-repair pathways to prevent cell cycle progression in response to DNA damage and replication stress [ 1 , 2 ].

It is worth noting that the Rad9 proteins referred to in this entry are the mammalian and fission yeast homologues of budding yeast Ddc1. Members of this family do not share the sequence homology another DNA damage-dependent checkpoint protein from budding yeast, confusingly also called Rad9.

In budding yeast, Ddc1 can activate Mec1 (the principal checkpoint protein kinase, human ATR homologue) in G1 phase. In G2 phase, Ddc1 can either activate Mec1 directly or recruit Dpb11 (the orthologue of human TopBP1) and subsequently activate Mec1 [ 3 ]. Ddc1 does not have DNA exonuclease function [ 4 ].

In humans, 9-1-1 binds to TopBP1 and activates the ATR-Chk1 checkpoint pathway [ 5 ]. Besides its function in the 9-1-1 complex, Rad9 can also act as a transcriptional factor and participate in immunoglobulin class switch recombination [ 6 ]. It also shows 3'-5' exonuclease activity [ 7 ]. Aberrant Rad9 expression has been associated with prostate, breast, lung, skin, thyroid, and gastric cancers [ 8 ].

1. The novel DNA damage checkpoint protein ddc1p is phosphorylated periodically during the cell cycle and in response to DNA damage in budding yeast. EMBO J. 16, 5216-26
2. 9-1-1: PCNA's specialized cousin. Trends Biochem. Sci. 36, 563-8
3. The unstructured C-terminal tail of the 9-1-1 clamp subunit Ddc1 activates Mec1/ATR via two distinct mechanisms. Mol. Cell 36, 743-53
4. Yeast Rad17/Mec3/Ddc1: a sliding clamp for the DNA damage checkpoint. Proc. Natl. Acad. Sci. U.S.A. 100, 2249-54
5. Two serine phosphorylation sites in the C-terminus of Rad9 are critical for 9-1-1 binding to TopBP1 and activation of the DNA damage checkpoint response in HeLa cells. Genes Cells 17, 807-16
6. Rad9 is required for B cell proliferation and immunoglobulin class switch recombination. J. Biol. Chem. 285, 35267-73
7. Human DNA damage checkpoint protein hRAD9 is a 3' to 5' exonuclease. J. Biol. Chem. 275, 7451-4
8. Contributions of Rad9 to tumorigenesis. J. Cell. Biochem. 113, 742-51