RAD9A (RAD9 homolog A (S. pombe))

2010-03-01   Vivian Chan 

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China




Atlas Image


6461 bp, 11 exons.


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


Atlas Image
(Adapted from Ishikawa K et al., Current Genomics.2006:7:477-80).


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.

Implicated in

Entity name
Various cancers
Checkpoint genes are known to be involved in the maintenance of genomic integrity and their aberrant expression can lead to cancer. Paralogue of human HRad9 is called HRad9B. Gene product is structurally related to hRad9 protein (55% similar and 35% identical). HRad9B gene is expressed predominantly in the testis and found in decreased amount in testicular tumours, particularly seminomas (Hopkins et al., 2003).
Entity name
Prostate cancer
Carboxy terminus of hRad9 contains a FXXLF motif which interrupts the androgen-induced interaction between the C and N terminus of androgen receptor (AR), acting as a co-regulator to suppress androgen-AR transactivation in prostrate cancer cells (Wang et al., 2004). This denotes a possible tumour suppressor function of hRad9.
Recent study has confirmed that high levels of Rad9 expression is found in prostate cancer cells and the high protein levels in prostate adenocarcinomas were generally associated with more advanced disease (Zhu et al., 2008). Similar to previous findings in breast cancer (Cheng et al., 2005), the increased expression of Rad9 in prostate cancer cells was in part due to aberrant methylation or gene amplification (Zhu et al., 2008). The study failed to show that the role of Rad9 in prostate tumorigenesis was androgen dependent, since both androgen dependent CWR22 and LNCaP cell lines as well as androgen independent DU145 and PC-3 cell lines were found to contain high levels of Rad9 protein (Zhu et al., 2008).
Entity name
Lung cancer
Presence of hyperphosphorylated forms of hRad9 has been found in the nuclei of surgically resected primary lung carcinoma cells (Maniwa et al., 2005). No mutation of the hRad9 gene was found in lung cancer cells, but a nonsynonymous single nucleotide polymorphism (SNP), His239Arg was found in 8 out of 50 lung adenocarcinoma patients, suggesting a possible association of this SNP with the development of cancer (Maniwa et al., 2006).
Entity name
Breast cancer
Over-expression of hRad9 mRNA was found in breast cancer, which was shown to be correlated with tumour size (p = 0.037) and local recurrence (p = 0.033). Over-expression of Rad9 mRNA was partly due to increase in RAD9 gene amplification and aberrant DNA methylation at a putative Sp 1/3 binding site within the second intron of the RAD9 gene. Promoter assays indicate that the Sp 1/3 site in intron 2 may act as a silencer. Further experiments in silencing Rad9 expression by RNAi inhibit the proliferation of MCF-7 cell line in vitro. These findings suggested that Rad9 is a new oncogene candidate on Ch11q13 with a role in breast cancer progression (Cheng et al., 2005).
In contrast to previous findings in testicular tumours, increased hRad9 protein was found in the nuclei of breast cancer cells. These were shown to exist as hyperphosphorylated forms, with molecular weights of 65 and 50 kDa. Since the theoretical molecular weight of hRad9 is 45 kDa (Lindsey-Boltz et al., 2001), these larger forms most likely represent hyperphosphorylated hRad9 and its hRad9-hRad1-hHus1 complex (Chan et al., 2008; St Onge et al., 1999). Localization of hyperphosphorylated forms of hRad in the nucleus of cancer cells is in keeping with its function in ameliorating DNA instability, whereby it inadvertently assists tumour growth.
Entity name
Colorectal cancer
Rad9 interacts physically within the DNA mismatch repair (MMR) protein MLH1. Disruption of the interaction by a single point mutation in Rad9 leads to significantly reduced mismatch repair activity (He et al., 2008). The Rad9-MHL1 interaction might be a hotspot for mutation in tumour cells. The hMLH1 mutations lead to hereditary non-polyposis colorectal cancer (HNPCC) (Avdievich et al., 2008; Peltomäki et al., 2004) and various types of tumours (Avdievich et al., 2008; Hu et al., 2008). However, hRad9s function in MMR is not in the 9-1-1-complex form (He et al., 2008).


Pubmed IDLast YearTitleAuthors
183375032008Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis.Avdievich E et al
107130442000Human DNA damage checkpoint protein hRAD9 is a 3' to 5' exonuclease.Bessho T et al
186168322008Localization of hRad9 in breast cancer.Chan V et al
112784462001ATM-dependent phosphorylation of human Rad9 is required for ionizing radiation-induced checkpoint activation.Chen MJ et al
162040322005The cell cycle checkpoint gene Rad9 is a novel oncogene activated by 11q13 amplification and DNA methylation in breast cancer.Cheng CK et al
194464812009Crystal structure of the rad9-rad1-hus1 DNA damage checkpoint complex--implications for clamp loading and regulation.Doré AS et al
129418022003hRad9 rapidly binds DNA containing double-strand breaks and is required for damage-dependent topoisomerase II beta binding protein 1 focus formation.Greer DA et al
188426332008Rad9 plays an important role in DNA mismatch repair through physical interaction with MLH1.He W et al
119943052002A role of the C-terminal region of human Rad9 (hRad9) in nuclear transport of the hRad9 checkpoint complex.Hirai I et al
145003602003Expression of mammalian paralogues of HRAD9 and Mrad9 checkpoint control genes in normal and cancerous testicular tissue.Hopkins KM et al
186326072008Targeted deletion of Rad9 in mouse skin keratinocytes enhances genotoxin-induced tumor development.Hu Z et al
183694032006Multiple functions of rad9 for preserving genomic integrity.Ishikawa K et al
106207992000Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis.Komatsu K et al
89430311996A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene.Lieberman HB et al
115729772001Purification and characterization of human DNA damage checkpoint Rad complexes.Lindsey-Boltz LA et al
164447452006His239Arg SNP of HRAD9 is associated with lung adenocarcinoma.Maniwa Y et al
190203052008ATR and Rad17 collaborate in modulating Rad9 localisation at sites of DNA damage.Medhurst AL et al
155287922004Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.Peltomäki P et al
108843952000The human checkpoint protein hRad17 interacts with the PCNA-like proteins hRad1, hHus1, and hRad9.Rauen M et al
127094422003Phosphorylation of human Rad9 is required for genotoxin-activated checkpoint signaling.Roos-Mattjus P et al
194642972009Crystal structure of the human rad9-hus1-rad1 clamp.Sohn SY et al
127341882003A role for the phosphorylation of hRad9 in checkpoint signaling.St Onge RP et al
153141872004The human Rad9/Rad1/Hus1 damage sensor clamp interacts with DNA polymerase beta and increases its DNA substrate utilisation efficiency: implications for DNA repair.Toueille M et al
98729891999Human homologs of Schizosaccharomyces pombe rad1, hus1, and rad9 form a DNA damage-responsive protein complex.Volkmer E et al
149662972004Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells.Wang L et al
151846592004Human RAD9 checkpoint control/proapoptotic protein can activate transcription of p21.Yin Y et al
126289352003Protein kinase Cdelta is responsible for constitutive and DNA damage-induced phosphorylation of Rad9.Yoshida K et al
183165882008Rad9 has a functional role in human prostate carcinogenesis.Zhu A et al
117990632002Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin.Zou L et al

Other Information

Locus ID:

NCBI: 5883
MIM: 603761
HGNC: 9827
Ensembl: ENSG00000172613


dbSNP: 5883
ClinVar: 5883
TCGA: ENSG00000172613


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
Activation of ATR in response to replication stressREACTOMER-HSA-176187
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
189361702008The basic cleft of RPA70N binds multiple checkpoint proteins, including RAD9, to regulate ATR signaling.87
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
164790042006Mammalian Rad9 plays a role in telomere stability, S- and G2-phase-specific cell survival, and homologous recombinational repair.78
153141872004The human Rad9/Rad1/Hus1 damage sensor clamp interacts with DNA polymerase beta and increases its DNA substrate utilisation efficiency: implications for DNA repair.57
126289352003Protein kinase Cdelta is responsible for constitutive and DNA damage-induced phosphorylation of Rad9.52
155569962004The human Rad9-Rad1-Hus1 checkpoint complex stimulates flap endonuclease 1.51
127094422003Phosphorylation of human Rad9 is required for genotoxin-activated checkpoint signaling.44
158716982005The human checkpoint sensor and alternative DNA clamp Rad9-Rad1-Hus1 modulates the activity of DNA ligase I, a component of the long-patch base excision repair machinery.37
127341882003A role for the phosphorylation of hRad9 in checkpoint signaling.36
195353282009Structure and functional implications of the human rad9-hus1-rad1 cell cycle checkpoint complex.36


Vivian Chan

RAD9A (RAD9 homolog A (S. pombe))

Atlas Genet Cytogenet Oncol Haematol. 2010-03-01

Online version: http://atlasgeneticsoncology.org/gene/42031/rad9a-(rad9-homolog-a-(s-pombe))