Alternative titles; symbols
HGNC Approved Gene Symbol: RAD17
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38) : 5:69,369,293-69,414,801 (from NCBI)
RAD17 is a checkpoint gene (Parker et al., 1998). Cell cycle checkpoints are complex signal transduction pathways that ensure the coordination of the timing and order of cell cycle events. These checkpoint pathways play critical roles in maintaining genomic stability and integrity to prevent the development of cancer and hereditary diseases (summary by Parker et al., 1998).
In the fission yeast Schizosaccharomyces pombe, the rad17 gene is required for both the DNA damage-dependent and the DNA replication-dependent cell cycle checkpoints. Parker et al. (1998) identified expressed sequence tags corresponding to a human homolog of S. pombe rad17. By PCR, they isolated a human SK-N-MC neuroblastoma cell cDNA containing the complete open reading frame of this homolog, RAD17. The deduced 670-amino acid RAD17 protein has a calculated molecular mass of 71 kD and has 20% sequence identity to S. pombe rad17. Northern blot analysis detected an approximately 3.0-kb transcript in all tissues examined, with elevated levels in testis and cancer cell lines. Although human RAD17 did not complement the checkpoint phenotypes of an S. pombe rad17 mutant, it interacted with human RAD1 (603153) in a yeast 2-hybrid system, and Parker et al. (1998) suggested that it is the homolog of S. pombe rad17.
Bao et al. (1998) cloned cDNAs encoding the mouse homolog of S. pombe rad17, which they called Rad24.
By microscopy, Bao et al. (1998) observed that green fluorescent protein-tagged Rad24 protein localized to the nucleus in living cells. Overexpression of wildtype Rad24 in human fibroblast cells caused a significant G2 arrest of the cell cycle, whereas overexpression of a mutant Rad24 protein that likely functions as a dominant-negative protein resulted in a defect in cell cycle arrest after DNA damage treatment. The authors suggested that the mammalian Rad24 protein may function as a critical gatekeeper in DNA damage checkpoint control.
With histologic studies based on in situ hybridization with radioactively labeled antisense RAD17 riboprobes, von Deimling et al. (1999) found strong expression of RAD17 within the germinal epithelium of the seminiferous tubuli in normal testis, but only weak, diffuse signals in testicular tumors (seminomas). In light of the known function of the yeast ortholog at meiotic and mitotic checkpoints, as well as the strong expression in testis and weak expression in seminomas, von Deimling et al. (1999) proposed involvement of RAD17 in testicular tumorigenesis.
Bao et al. (2001) demonstrated a direct regulatory linkage between RAD17 and the checkpoint kinases ATM (607585) and ATR (601215). Treatment of human cells with genotoxic agents induced ATM/ATR-dependent phosphorylation of RAD17 at serine-635 and serine-645. Overexpression of a RAD17 mutant bearing alanine substitutions at both phosphorylation sites abrogated the DNA damage-induced G2 checkpoint and sensitized human fibroblasts to genotoxic stress. In contrast to wildtype RAD17, the RAD17 mutant showed no ionizing radiation-inducible association with RAD1 (603153), a component of the RAD1-RAD9 (603761)-HUS1 (603760) checkpoint complex. These findings demonstrated that ATR/ATM-dependent phosphorylation of RAD17 is a critical early event during checkpoint signaling in DNA-damaged cells.
Wang et al. (2006) found that phosphorylated RAD17 interacted with claspin (CLSPN; 605434), a protein critical for replication stress-induced CHK1 (CHEK1; 603078) activation, and regulated its phosphorylation. Phosphorylation of RAD17 was differentially required in response to different DNA-damaging agents and was particularly important in stress due to hydroxyurea exposure.
By FISH, Parker et al. (1998) localized the RAD17 gene to 4q13.3-q21.2; however, in an erratum, they stated that this localization was in error and that the true location of RAD17 is 5q13 by FISH and radiation hybrid analysis. The error had been made in the identification of the chromosome labeled by FISH as chromosome 4 rather than chromosome 5 (due to similar DAPI banding pattern). Bao et al. (1999) independently mapped the RAD17 gene to 5q12-q13.1. Three other groups mapped the RAD17 gene to 5q13 by FISH (Dean et al., 1998; Bluyssen et al., 1999; von Deimling et al., 1999).
Von Deimling et al. (1999) mapped the mouse Rad17 gene to distal chromosome 13. They found that the gene in both human and mouse is located between GTF2H2 (601748), called Btf2p44 in the mouse, and cyclin B1 (CCNB1; 123836).
Bao, S., Chang, M.-S., Auclair, D., Sun, Y., Wang, Y., Wong, W.-K., Zhang, J., Liu, Y., Qian, X., Sutherland, R., Magi-Galluzi, C., Weisberg, E., Cheng, E. Y. S., Hao, L., Sasaki, H., Campbell, M. S., Kraeft, S.-K., Loda, M., Lo, K.-M., Chen, L. B. Hrad17, a human homologue of the Schizosaccharomyces pombe checkpoint gene rad17, is overexpressed in colon carcinoma. Cancer Res. 59: 2023-2028, 1999. [PubMed: 10232579]
Bao, S., Shen, X., Shen, K., Liu, Y., Wang, X.-F. The mammalian Rad24 homologous to yeast Saccharomyces cerevisiae Rad24 and Schizosaccharomyces pombe Rad17 is involved in DNA damage checkpoint. Cell Growth Diff. 9: 961-967, 1998. [PubMed: 9869296]
Bao, S., Tibbetts, R. S., Brumbaugh, K. M., Fang, Y., Richardson, D. A., Ali, A., Chen, S. M., Abraham, R. T., Wang, X.-F. ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature 411: 969-974, 2001. [PubMed: 11418864] [Full Text: https://doi.org/10.1038/35082110]
Bluyssen, H. A. R., Naus, N. C., van Os, R. I., Jaspers, I., Hoeijmakers, J. H. J., de Klein, A. Human and mouse homologues of the Schizosaccharomyces pombe rad17+ cell cycle checkpoint control gene. Genomics 55: 219-228, 1999. [PubMed: 9933569] [Full Text: https://doi.org/10.1006/geno.1998.5642]
Dean, F. B., Lian, L., O'Donnell, M. cDNA cloning and gene mapping of human homologs for Schizosaccharomyces pombe rad17, rad1, and hus1 and cloning of homologs from mouse, Caenorhabditis elegans, and Drosophila melanogaster. Genomics 54: 424-436, 1998. [PubMed: 9878245] [Full Text: https://doi.org/10.1006/geno.1998.5587]
Parker, A. E., Van de Weyer, I., Laus, M. C., Verhasselt, P., Luyten, W. H. M. L. Identification of a human homologue of the Schizosaccharomyces pombe rad17+ checkpoint gene. J. Biol. Chem. 273: 18340-18346, 1998. Note: Erratum: J. Biol. Chem. 274: 24438-24439, 1999. [PubMed: 9660800] [Full Text: https://doi.org/10.1074/jbc.273.29.18340]
von Deimling, F., Scharf, J. M., Liehr, T., Rothe, M., Kelter, A.-R., Albers, P., Dietrich, W. F., Kunkel, L. M., Wernert, N., Wirth, B. Human and mouse RAD17 genes: identification, localization, genomic structure and histological expression pattern in normal testis and seminoma. Hum. Genet. 105: 17-27, 1999. [PubMed: 10480350] [Full Text: https://doi.org/10.1007/s004399900067]
Wang, X., Zou, L., Lu, T., Bao, S., Hurov, K. E., Hittelman, W. N., Elledge, S. J., Li, L. Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress. Molec. Cell 23: 331-341, 2006. [PubMed: 16885023] [Full Text: https://doi.org/10.1016/j.molcel.2006.06.022]