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Gene Review

HUS1  -  HUS1 checkpoint homolog (S. pombe)

Homo sapiens

Synonyms: Checkpoint protein HUS1, hHUS1
 
 
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Disease relevance of HUS1

  • Introduction of exogenous Fhit into cells in vitro led to modulation of expression of checkpoint proteins Hus1 and Chk1 at mid-S checkpoint, a modulation that led to induction of apoptosis in esophageal cancer cells but not in noncancerous primary cultures [1].
 

High impact information on HUS1

  • These findings demonstrate that PKCdelta is responsible for the regulation of Rad9 in the Hus1-Rad1 complex and in the apoptotic response to DNA damage [2].
  • This mutant protein is able to associate with all three replicative polymerases and checkpoint proteins Rad3ATR-Rad26ATRIP, Hus1, Rad9, and Rad17 but has a compromised association with Crb3 [3].
  • Here we report that the mammalian Rad9/Rad1/Hus1 (911) checkpoint complex, which localizes to sites of genome damage and promotes DDR signaling, is an integral component of the telomere in human and mouse cells [4].
  • By the use of quantitative telomere-length measurements, we demonstrate severe telomeric shortening in both Hus1-deficient mouse embryonic fibroblasts and thymocytes from conditional Hus1-knockout mice [4].
  • Rad9, Rad1, and Hus1 are members of the Rad family of checkpoint proteins that are required for both DNA replication and DNA damage checkpoints and are thought to function as sensors in the DNA integrity checkpoint control [5].
 

Biological context of HUS1

  • The major focus of this report is on a detailed analysis of the physical interactions of the HUS1-encoded protein and two other checkpoint control proteins, RAD1p and RAD9p, implicated in the cellular response to DNA damage [6].
  • Identification and characterization of a paralog of human cell cycle checkpoint gene HUS1 [7].
  • Furthermore, overexpression of HUS1B but not HUS1 in human cells induces clonogenic cell death [7].
  • Growing evidence suggests that the Rad9/Rad1/Hus1 cell-cycle checkpoint complex (9-1-1 complex), which is recruited to DNA lesion upon DNA damage, plays a major role in DNA repair [8].
  • Schizosaccharomyces pombe hus1 promotes radioresistance and hydroxyurea resistance, as well as S and G2 phase checkpoint control [6].
 

Anatomical context of HUS1

  • Northern blot analysis indicates that HUS1 is expressed in different tissues, but the mRNA is most predominant in testis where high levels of RAD1 and RAD9 message have been detected [6].
  • For hRAD9, hHUS1 or CHK1, no SSCP variant was detected in any of the cell lines tested, indicating a high stability of these genes in human cancer [9].
  • Furthermore, our studies reveal a new function of HUS-1 in the prevention of telomere shortening and mortalization of germ cells [10].
 

Associations of HUS1 with chemical compounds

  • The growth and viability of cells treated with Hus1 antisense oligonucleotides in the presence or absence of cisplatin were analyzed and compared to controls [11].
  • METHODS: Transfection of 2'-O-methoxyethyl-modified Hus1 antisense oligoribonucleotides into human H1299 nonsmall lung carcinoma cells was performed using Lipofectin as the carrier [11].
  • Thus, HUS-1 is required for p53-dependent activation of a BH3 domain protein in C. elegans [10].
 

Physical interactions of HUS1

  • In addition, we have also shown that RAD9 and RAD9B interact with the HUS1 paralog, HUS1B [12].
  • Interaction and colocalization of Rad9/Rad1/Hus1 checkpoint complex with replication protein A in human cells [13].
  • The current model in human predicts, that a Rad17/Replication factor C (RF-C) complex might serve as a recruitment complex for the Rad9/Hus1/Rad1 complex to sites of replication block or DNA damage [14].
 

Other interactions of HUS1

  • We show here that the human checkpoint control protein hRAD9 physically associates with two other checkpoint control proteins, hRAD1 and hHUS1 [15].
  • HUS1B is less conserved evolutionarily than HUS1 [7].
  • Human HDAC1 was found to interact specifically in yeast, mammalian cells, and in vitro with the human Hus1 gene product, whose Schizosaccharomyces pombe homolog has been implicated in G(2)/M checkpoint control [16].
  • Using a yeast two-hybrid system to detect protein-protein interactions, we found that human proliferating cell nuclear antigen (PCNA), a protein known to function in both DNA replication and repair, interacts with the human checkpoint-related protein Hus1 (hHus1) [17].
  • Chk1 is phosphorylated on Ser-317 and Ser-345 following a checkpoint signal, a process that is regulated by Atr, and by the sensor complexes containing Rad17 and Hus1 [18].
 

Analytical, diagnostic and therapeutic context of HUS1

  • Three of the proteins involved in checkpoint signaling, Rad1, Hus1, and Rad9, have been shown to interact by immunoprecipitation and yeast two-hybrid studies [19].

References

  1. Fhit modulates the DNA damage checkpoint response. Ishii, H., Mimori, K., Inoue, H., Inageta, T., Ishikawa, K., Semba, S., Druck, T., Trapasso, F., Tani, K., Vecchione, A., Croce, C.M., Mori, M., Huebner, K. Cancer Res. (2006) [Pubmed]
  2. Protein kinase Cdelta is responsible for constitutive and DNA damage-induced phosphorylation of Rad9. Yoshida, K., Wang, H.G., Miki, Y., Kufe, D. EMBO J. (2003) [Pubmed]
  3. Rad4TopBP1, a scaffold protein, plays separate roles in DNA damage and replication checkpoints and DNA replication. Taricani, L., Wang, T.S. Mol. Biol. Cell (2006) [Pubmed]
  4. Telomere and telomerase modulation by the mammalian Rad9/Rad1/Hus1 DNA-damage-checkpoint complex. Francia, S., Weiss, R.S., Hande, M.P., Freire, R., d'Adda di Fagagna, F. Curr. Biol. (2006) [Pubmed]
  5. A role of the C-terminal region of human Rad9 (hRad9) in nuclear transport of the hRad9 checkpoint complex. Hirai, I., Wang, H.G. J. Biol. Chem. (2002) [Pubmed]
  6. Physical interactions among human checkpoint control proteins HUS1p, RAD1p, and RAD9p, and implications for the regulation of cell cycle progression. Hang, H., Lieberman, H.B. Genomics (2000) [Pubmed]
  7. Identification and characterization of a paralog of human cell cycle checkpoint gene HUS1. Hang, H., Zhang, Y., Dunbrack, R.L., Wang, C., Lieberman, H.B. Genomics (2002) [Pubmed]
  8. The two DNA clamps Rad9/Rad1/Hus1 complex and proliferating cell nuclear antigen differentially regulate flap endonuclease 1 activity. Friedrich-Heineken, E., Toueille, M., Tännler, B., Bürki, C., Ferrari, E., Hottiger, M.O., Hübscher, U. J. Mol. Biol. (2005) [Pubmed]
  9. Determination of the genotype of a panel of human tumor cell lines for the human homologues of yeast cell cycle checkpoint control genes: identification of cell lines carrying homoallelic missense base substitutions. Ejima, Y., Yang, L. Somat. Cell Mol. Genet. (1999) [Pubmed]
  10. Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Hofmann, E.R., Milstein, S., Boulton, S.J., Ye, M., Hofmann, J.J., Stergiou, L., Gartner, A., Vidal, M., Hengartner, M.O. Curr. Biol. (2002) [Pubmed]
  11. Downregulation of Hus1 by antisense oligonucleotides enhances the sensitivity of human lung carcinoma cells to cisplatin. Kinzel, B., Hall, J., Natt, F., Weiler, J., Cohen, D. Cancer (2002) [Pubmed]
  12. Identification and characterization of RAD9B, a paralog of the RAD9 checkpoint gene. Dufault, V.M., Oestreich, A.J., Vroman, B.T., Karnitz, L.M. Genomics (2003) [Pubmed]
  13. Interaction and colocalization of Rad9/Rad1/Hus1 checkpoint complex with replication protein A in human cells. Wu, X., Shell, S.M., Zou, Y. Oncogene (2005) [Pubmed]
  14. Colocalization of human Rad17 and PCNA in late S phase of the cell cycle upon replication block. Dahm, K., Hübscher, U. Oncogene (2002) [Pubmed]
  15. The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. St Onge, R.P., Udell, C.M., Casselman, R., Davey, S. Mol. Biol. Cell (1999) [Pubmed]
  16. HDAC1, a histone deacetylase, forms a complex with Hus1 and Rad9, two G2/M checkpoint Rad proteins. Cai, R.L., Yan-Neale, Y., Cueto, M.A., Xu, H., Cohen, D. J. Biol. Chem. (2000) [Pubmed]
  17. PCNA interacts with hHus1/hRad9 in response to DNA damage and replication inhibition. Komatsu, K., Wharton, W., Hang, H., Wu, C., Singh, S., Lieberman, H.B., Pledger, W.J., Wang, H.G. Oncogene (2000) [Pubmed]
  18. Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345. Jiang, K., Pereira, E., Maxfield, M., Russell, B., Goudelock, D.M., Sanchez, Y. J. Biol. Chem. (2003) [Pubmed]
  19. Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9-1-1) DNA damage responsive checkpoint complex. Burtelow, M.A., Roos-Mattjus, P.M., Rauen, M., Babendure, J.R., Karnitz, L.M. J. Biol. Chem. (2001) [Pubmed]
 
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