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Gene Review

EXO1  -  exonuclease 1

Homo sapiens

Synonyms: EXOI, Exonuclease 1, Exonuclease I, HEX1, hExo1, ...
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Disease relevance of EXO1


High impact information on EXO1

  • Cleaved single-strand tails will be processed by error-prone DNA polymerase-mediated gap-filling or exonuclease-mediated resection [4].
  • A mismatch-containing DNA segment spanned by two strand breaks is removed by the 5'-to-3' activity of MutSalpha-activated exonuclease I. The probable endonuclease active site has been localized to a PMS2 DQHA(X)(2)E(X)(4)E motif [5].
  • The upstream cleavage product corresponds to the mature histone mRNA, while the downstream product is degraded by a 5'-3' exonuclease, also dependent on the U7 snRNP [6].
  • The purified Artemis protein alone possesses single-strand-specific 5' to 3' exonuclease activity [7].
  • These structures unify Mre11's multiple nuclease activities in a single endo/exonuclease mechanism and reveal eukaryotic macromolecular interaction sites by mapping human and yeast Mre11 mutations [8].

Chemical compound and disease context of EXO1

  • Deletions into each end of the adenovirus inverted terminal repeat (ITR) were generated with Bal31 exonuclease and the resulting molecules constructed into plasmids which contained two inverted copies of the deleted ITR separated by the bacterial neomycin phosphotransferase gene [9].
  • We have investigated the mechanistic basis for the differential toxicity of these three cytosine analogs by comparing the effects of dideoxy-CTP), (+)3TC-triphosphate (TP), and (-)3TC-TP on the polymerase and exonuclease activities of recombinant human Pol gamma [10].
  • The method was verified with the ternary 30 kDa complex between the lanthanide-labeled N-terminal domain of the epsilon exonuclease subunit from the Escherichia coli DNA polymerase III, the subunit theta, and thymidine [11].
  • Using an in vivo Exonuclease III footprinting assay, we found that estrogen stimulation of MCF-7 cells induced loading of a transcription factor(s) to a portion of the promoter (-124 to -104) that is homologous to the adenovirus major late promoter element [12].
  • The requirements for expression of genes under the control of early (alkaline exonuclease) and late (VP5) herpes simplex virus type 1 (HSV-1) gene promoters were examined in a transient expression assay, using the bacterial chloramphenicol acetyltransferase gene as an expression marker [13].

Biological context of EXO1

  • METHODS: All 14 exons of EXO1 were scanned for mutations in index patients from 33 families with HNPCC fulfilling the Amsterdam criteria and in 225 index patients suspected of HNPCC [1].
  • To determine its role in HNPCC, EXO1 was scanned for germline mutations [1].
  • RESULTS: Germline variants of EXO1 were detected in 14 patients, including one splice-site mutation in a family with HNPCC and 13 missense mutations in patients with atypical HNPCC [1].
  • Heterozygosity analysis showed one case without EXO1 allelic loss and 12 tumors with loss of the mutant allele and retention of the normal one [1].
  • Human exonuclease 1 (hExo1) possesses both 5'exonuclease and flap endonuclease activities and plays a role in DNA repair, recombination, and replication [14].

Anatomical context of EXO1

  • The hExoI cDNA comprises 2541 bp, which code for a Mr 94,000 protein that appears to be highly expressed in testis tissue and at very low levels in other tissues [15].
  • Northern blot analysis demonstrates that hEXO1 is expressed in high levels in testis; elevated expression was also observed in thymus and colon and to a lesser extent in small intestine, placenta, spleen, and ovary [16].
  • Northern blot analysis also revealed that hEXO1/HEX1 is highly expressed in several liver cancer cell lines as well as in colon and pancreas adenocarcinomas, but not in the corresponding non-neoplastic tissue [17].
  • Northern blot analysis revealed that HEX1 expression is highest in fetal liver and adult bone marrow, suggesting that the encoded protein may operate prominently in processes specific to hemopoietic stem cell development [18].
  • WRN, which functions in cellular recombination pathways via its helicase and exonuclease activities, is not absolutely required for viral replication, as viral yields are only very slightly, if at all, decreased in WRN-deficient human primary fibroblasts compared to control cells [19].

Associations of EXO1 with chemical compounds


Physical interactions of EXO1


Enzymatic interactions of EXO1


Regulatory relationships of EXO1

  • The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein [34].
  • The 3'-5' exonuclease activity was stimulated 8-10 fold by the addition of HSSB, and this stimulatory effect was preferential to HSSB since other SSBs from E. coli, T4 or adenovirus, had a little or no effect [35].
  • Functionally, BLM inhibited the exonuclease activity of WRN [36].
  • HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes [37].
  • Consistent with recent evidence, we have assembled a novel cell-cycle-dependent model in which DNA-PK inhibits RPA in S-phase of the cell cycle, while BRCA1 inhibits the exonuclease processivity of the MRE11/RAD50/NBS1 (MRN) complex and facilitates the removal of RPA in S and G2 phase [38].

Other interactions of EXO1

  • Thus, the genomic instability observed in WRN-/- cells may be at least partially attributed to the lack of interactions between the WRN protein and human nucleases including EXO-1 [34].
  • Although the role of EXO-1 is not well understood, its 5' to 3'-exonuclease and flap endonuclease activities may cleave intermediates that arise during DNA metabolism [34].
  • Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA [39].
  • We also show that both hMLH1-hPMS2 (MutLalpha) and hMLH1-hEXO1 complexes are formed in a reaction mixture containing all three proteins [39].
  • We report here a novel interaction of the BLM protein with the human 5'-flap endonuclease/5'-3' exonuclease (FEN-1), a genome stability factor involved in Okazaki fragment processing and DNA repair [40].

Analytical, diagnostic and therapeutic context of EXO1


  1. Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. Wu, Y., Berends, M.J., Post, J.G., Mensink, R.G., Verlind, E., Van Der Sluis, T., Kempinga, C., Sijmons, R.H., van der Zee, A.G., Hollema, H., Kleibeuker, J.H., Buys, C.H., Hofstra, R.M. Gastroenterology (2001) [Pubmed]
  2. Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability. Alam, N.A., Gorman, P., Jaeger, E.E., Kelsell, D., Leigh, I.M., Ratnavel, R., Murdoch, M.E., Houlston, R.S., Aaltonen, L.A., Roylance, R.R., Tomlinson, I.P. Cancer Genet. Cytogenet. (2003) [Pubmed]
  3. Single nucleotide polymorphisms in the EXO1 gene and risk of colorectal cancer in a Japanese population. Yamamoto, H., Hanafusa, H., Ouchida, M., Yano, M., Suzuki, H., Murakami, M., Aoe, M., Shimizu, N., Nakachi, K., Shimizu, K. Carcinogenesis (2005) [Pubmed]
  4. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Honjo, T., Kinoshita, K., Muramatsu, M. Annu. Rev. Immunol. (2002) [Pubmed]
  5. Endonucleolytic function of MutLalpha in human mismatch repair. Kadyrov, F.A., Dzantiev, L., Constantin, N., Modrich, P. Cell (2006) [Pubmed]
  6. The polyadenylation factor CPSF-73 is involved in histone-pre-mRNA processing. Dominski, Z., Yang, X.C., Marzluff, W.F. Cell (2005) [Pubmed]
  7. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Ma, Y., Pannicke, U., Schwarz, K., Lieber, M.R. Cell (2002) [Pubmed]
  8. Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Hopfner, K.P., Karcher, A., Craig, L., Woo, T.T., Carney, J.P., Tainer, J.A. Cell (2001) [Pubmed]
  9. The origin of adenovirus DNA replication: minimal DNA sequence requirement in vivo. Hay, R.T. EMBO J. (1985) [Pubmed]
  10. Insights into the molecular mechanism of mitochondrial toxicity by AIDS drugs. Feng, J.Y., Johnson, A.A., Johnson, K.A., Anderson, K.S. J. Biol. Chem. (2001) [Pubmed]
  11. Structure determination of protein-ligand complexes by transferred paramagnetic shifts. John, M., Pintacuda, G., Park, A.Y., Dixon, N.E., Otting, G. J. Am. Chem. Soc. (2006) [Pubmed]
  12. Upstream stimulatory factors mediate estrogen receptor activation of the cathepsin D promoter. Xing, W., Archer, T.K. Mol. Endocrinol. (1998) [Pubmed]
  13. Virus-induced modification of the host cell is required for expression of the bacterial chloramphenicol acetyltransferase gene controlled by a late herpes simplex virus promoter (VP5). Costa, R.H., Draper, K.G., Devi-Rao, G., Thompson, R.L., Wagner, E.K. J. Virol. (1985) [Pubmed]
  14. Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome. Sun, X., Zheng, L., Shen, B. Cancer Res. (2002) [Pubmed]
  15. Human exonuclease I interacts with the mismatch repair protein hMSH2. Schmutte, C., Marinescu, R.C., Sadoff, M.M., Guerrette, S., Overhauser, J., Fishel, R. Cancer Res. (1998) [Pubmed]
  16. Identification of a human gene encoding a homologue of Saccharomyces cerevisiae EXO1, an exonuclease implicated in mismatch repair and recombination. Tishkoff, D.X., Amin, N.S., Viars, C.S., Arden, K.C., Kolodner, R.D. Cancer Res. (1998) [Pubmed]
  17. Identification of factors interacting with hMSH2 in the fetal liver utilizing the yeast two-hybrid system. In vivo interaction through the C-terminal domains of hEXO1 and hMSH2 and comparative expression analysis. Rasmussen, L.J., Rasmussen, M., Lee, B., Rasmussen, A.K., Wilson, D.M., Nielsen, F.C., Bisgaard, H.C. Mutat. Res. (2000) [Pubmed]
  18. Hex1: a new human Rad2 nuclease family member with homology to yeast exonuclease 1. Wilson, D.M., Carney, J.P., Coleman, M.A., Adamson, A.W., Christensen, M., Lamerdin, J.E. Nucleic Acids Res. (1998) [Pubmed]
  19. Proteomics of herpes simplex virus replication compartments: association of cellular DNA replication, repair, recombination, and chromatin remodeling proteins with ICP8. Taylor, T.J., Knipe, D.M. J. Virol. (2004) [Pubmed]
  20. The RAD2 domain of human exonuclease 1 exhibits 5' to 3' exonuclease and flap structure-specific endonuclease activities. Lee, B.I., Wilson, D.M. J. Biol. Chem. (1999) [Pubmed]
  21. Concerted Action of Exonuclease and Gap-dependent Endonuclease Activities of FEN-1 Contributes to the Resolution of Triplet Repeat Sequences (CTG)n- and (GAA)n-derived Secondary Structures Formed during Maturation of Okazaki Fragments. Singh, P., Zheng, L., Chavez, V., Qiu, J., Shen, B. J. Biol. Chem. (2007) [Pubmed]
  22. Werner syndrome protein phosphorylation by abl tyrosine kinase regulates its activity and distribution. Cheng, W.H., von Kobbe, C., Opresko, P.L., Fields, K.M., Ren, J., Kufe, D., Bohr, V.A. Mol. Cell. Biol. (2003) [Pubmed]
  23. Biochemical characterization of an exonuclease from Arabidopsis thaliana reveals similarities to the DNA exonuclease of the human Werner syndrome protein. Plchova, H., Hartung, F., Puchta, H. J. Biol. Chem. (2003) [Pubmed]
  24. Biochemical and kinetic characterization of the DNA helicase and exonuclease activities of werner syndrome protein. Choudhary, S., Sommers, J.A., Brosh, R.M. J. Biol. Chem. (2004) [Pubmed]
  25. The interaction of DNA mismatch repair proteins with human exonuclease I. Schmutte, C., Sadoff, M.M., Shim, K.S., Acharya, S., Fishel, R. J. Biol. Chem. (2001) [Pubmed]
  26. Werner syndrome protein. I. DNA helicase and dna exonuclease reside on the same polypeptide. Shen, J.C., Gray, M.D., Oshima, J., Kamath-Loeb, A.S., Fry, M., Loeb, L.A. J. Biol. Chem. (1998) [Pubmed]
  27. Identification of the human HEX1/hExo1 gene promoter and characterization of elements responsible for promoter activity. Ladd, P.D., Wilson, D.M., Kelley, M.R., Skalnik, D.G. DNA Repair (Amst.) (2003) [Pubmed]
  28. A defined human system that supports bidirectional mismatch-provoked excision. Dzantiev, L., Constantin, N., Genschel, J., Iyer, R.R., Burgers, P.M., Modrich, P. Mol. Cell (2004) [Pubmed]
  29. Multiple but dissectible functions of FEN-1 nucleases in nucleic acid processing, genome stability and diseases. Shen, B., Singh, P., Liu, R., Qiu, J., Zheng, L., Finger, L.D., Alas, S. Bioessays (2005) [Pubmed]
  30. Exogenous expression of exonuclease domain-deleted WRN interferes with the repair of radiation-induced DNA damages. Kashino, G., Kodama, S., Suzuki, K., Matsumoto, T., Watanabe, M. J. Radiat. Res. (2005) [Pubmed]
  31. 3 -5 exonuclease activity of human apurinic/apyrimidinic endonuclease 1 towards DNAs containing dNMP and their modified analogs at the 3 end of single strand DNA break. Dyrkheeva, N.S., Khodyreva, S.N., Sukhanova, M.V., Safronov, I.V., Dezhurov, S.V., Lavrik, O.I. Biochemistry Mosc. (2006) [Pubmed]
  32. Efficiency of exonucleolytic action of apurinic/apyrimidinic endonuclease 1 towards matched and mismatched dNMP at the 3' terminus of different oligomeric DNA structures correlates with thermal stability of DNA duplexes. Dyrkheeva, N.S., Lomzov, A.A., Pyshnyi, D.V., Khodyreva, S.N., Lavrik, O.I. Biochim. Biophys. Acta (2006) [Pubmed]
  33. In situ fluorescent nick translation procedure for plant chromosomes. Luchniak, P., Maluszynska, J., Olszewska, M.J. Biotechnic & histochemistry : official publication of the Biological Stain Commission. (2002) [Pubmed]
  34. The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. Sharma, S., Sommers, J.A., Driscoll, H.C., Uzdilla, L., Wilson, T.M., Brosh, R.M. J. Biol. Chem. (2003) [Pubmed]
  35. The 3'-5' exonuclease of human DNA polymerase delta (pol delta) is regulated by pol delta accessory factors and deoxyribonucleoside triphosphates. Lee, S.H. Nucleic Acids Res. (1993) [Pubmed]
  36. Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. von Kobbe, C., Karmakar, P., Dawut, L., Opresko, P., Zeng, X., Brosh, R.M., Hickson, I.D., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  37. HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes. Jäger, A.C., Rasmussen, M., Bisgaard, H.C., Singh, K.K., Nielsen, F.C., Rasmussen, L.J. Oncogene (2001) [Pubmed]
  38. Good timing in the cell cycle for precise DNA repair by BRCA1. Durant, S.T., Nickoloff, J.A. Cell Cycle (2005) [Pubmed]
  39. Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA. Nielsen, F.C., Jäger, A.C., Lützen, A., Bundgaard, J.R., Rasmussen, L.J. Oncogene (2004) [Pubmed]
  40. Stimulation of flap endonuclease-1 by the Bloom's syndrome protein. Sharma, S., Sommers, J.A., Wu, L., Bohr, V.A., Hickson, I.D., Brosh, R.M. J. Biol. Chem. (2004) [Pubmed]
  41. p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex. Chen, U., Chen, S., Saha, P., Dutta, A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  42. A new DNA polymerase species from Drosophila melanogaster: a probable mus308 gene product. Oshige, M., Aoyagi, N., Harris, P.V., Burtis, K.C., Sakaguchi, K. Mutat. Res. (1999) [Pubmed]
  43. Molecular interactions of human Exo1 with DNA. Lee Bi, B.I., Nguyen, L.H., Barsky, D., Fernandes, M., Wilson, D.M. Nucleic Acids Res. (2002) [Pubmed]
  44. Enhancer-origin interaction in plasmid R6K involves a DNA loop mediated by initiator protein. Mukherjee, S., Erickson, H., Bastia, D. Cell (1988) [Pubmed]
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