RAD9A (RAD9 homolog A (S. pombe))

Description	6461 bp, 11 exons.
Transcription	The transcript length is 1176 bp, full open reading frame cDNA clone, encodes a 391 amino acid, 42520 Da protein (Lieberman et al., 1996).

	(Adapted from Ishikawa K et al., Current Genomics.2006:7:477-80).
Function	The gene product is highly similar to Rad9 protein from S pombe. A cell cycle checkpoint protein with multiple functions for preserving genomic integrity (Ishikawa et al., 2006), such as the regulation of DNA damage response, cell cycle checkpoint, DNA repair, apoptosis, transcriptional regulation, exonuclease activity, ribonucleotide synthesis and embryogenesis. hRad9 forms ring-shape heterotrimeric complex with hRad1 and hHus1 proteins (9-1-1 complex). All 3 proteins have sequence homology with proliferating cell nuclear antigen (PCNA). The 9-1-1 complex is recruited onto DNA-lesion by RAD17 and ATR - triggering checkpoint signaling pathway and acts to repair DNA damage (Volkmer and Karnitz, 1999; Rauen et al., 2000; Zou et al., 2002; Medhurst et al., 2008). Phosphorylation of hRad9 by protein kinase C delta (PKCD) is necessary for the formation of the 9-1-1 complex (Yoshida et al., 2003). NH2 terminus of hRad9 contains BH3-like domain which binds antiapoptotic proteins BCL2 and Bcl-x2, thereby promoting apoptosis (Komatsu et al., 2000). This interaction of hRad9 to Bcl2 is regulated also by PKCdelta (Yoshida et al., 2003). RAD9, like P53 can regulate P21 at the transcriptional level. Overexpression of hRad was shown to cause an increase in P21 RNA and the encoded protein level in P53-null H1299 cells (Yin et al., 2004). This suggests that hRAD9 and P53 coregulate P21 to direct cell cycle progression. hRAD9 may also modulate transcription of other down-stream target genes. C-terminal region of hRad9 protein acts to transport 9-1-1 complex into the nucleus (Hirai and Wang, 2002; Sohn and Cho, 2009). hRad9 and ATM rapidly colocalize to regions containing DNA double-stranded breaks after DNA-damage (Greer et al., 2003; Medhurst et al., 2008) and Atm can phosphorylate Rad9 directly at Ser-272 during ionizing radiation (IR)-induced G1/S checkpoint activation (Chen et al., 2001). The 9-1-1 complex may attract DNA polymerase beta to sites of DNA damage, thus connecting checkpoint and DNA repair (Toueille et al., 2004). Thr-292 of hRad9 is subject to CDC2-dependent phosphorylation in mitosis. Four other hRad9 phosphorylation sites (Ser-277, Ser-328, Ser-336 and Thr-355) are regulated in part by Cdc2 (St Onge et al., 2001; St Onge et al., 2003; Ishikawa et al., 2006). Phosphorylation sites of the C-terminal region of hRad9 are essential for CHK1 activation following hydroxyurea, ionizing radiation and ultraviolet treatment (Roos-Mattjus et al., 2003). Crystal structure of the human Rad9-Hus1-Rad1 complex reveals a single repair enzyme binding site (Doré et al., 2009) and suggests that the C-terminal end of Rad9 protein is involved in the regulation of the complex in DNA binding (Sohn and Cho, 2009). hRad9 possesses 3'-5' exonuclease activity which may contribute to its role in sensing and repairing DNA damage (Bessho and Sancar, 2000). The exact mechanism of this exonucleolytic processing is still unclear.

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