RAD9 encodes an adaptor protein required for S. cerevisiae cell cycle checkpoint function. By mediating phosphorylation of important effector kinases, Rad9p facilitates the amplification of initial signals in response to DNA damage (reviewed in 2). Because of the ability of Rad9p to associate with double-stranded breaks, it is speculated that Rad9p also initiates these checkpoint signal transduction cascades by acting as a DNA damage sensor (6). Rad9p is required throughout the cell cycle; it has been shown to function at G1/S, intra-S, and G2/M (7, 8, 9).

Rad9p is phosphorylated during normal progression of the cell cycle, but becomes hyperphosphorylated by Mec1p and Tel1p in response to DNA damage (10, 11). Activated Rad9p then stimulates Mec1p phosphorylation of the effector kinases Chk1p and Rad53p (12, 13, 14). Chk1p and Rad53p phosphorylation leads to various processes associated with cellular arrest, such as transcriptional upregulation of DNA damage repair genes, transcriptional repression of cyclins, and stabilization of replication forks (reviewed in 15 and 16).

Rad9p has two BRCT (BRCA1 C-terminus) domains in its C-terminus that facilitate Rad9p-Rad9p interaction after DNA damage (17). It also has a tandem tudor domain that binds to double-stranded DNA (18). Rad9p purifies in two distinct complexes, a larger 850 kDa complex and a smaller 560 kDa complex. In addition to Rad9p, both complexes contain the chaperone proteins Ssa1p and Ssa2p and the smaller complex also includes Rad53p (19).

RAD9 null mutants are viable but exhibit sensitivity to X-ray and UV irradation, fail to arrest in response to DNA damage, and are prone to chromosomal instability (9, 20, 21). The RAD9 ortholog in S. pombe is crb2 (22). No single human ortholog has been identified; instead, in humans there exists a family of proteins, which includes BRCA1 (OMIM) and 53BP1 (OMIM), that contain tandem BRCT domains (23, 24). S. pombe crb2 and human 53BP1, like Rad9p, also contain tandem tudor domains (18).

Last updated: 2008-10-21