Exonuclease 1 Explained

Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.^{[1] [2] [3]}

This gene encodes a protein with 5' to 3' exonuclease activity as well as RNase activity (endonuclease activity cleaving RNA on DNA/RNA hybrid).^[4] It is similar to the Saccharomyces cerevisiae protein Exo1 which interacts with Msh2 and which is involved in DNA mismatch repair and homologous recombination. Alternative splicing of this gene results in three transcript variants encoding two different isoforms.^[3]

Meiosis

ExoI is essential for meiotic progression through metaphase I in the budding yeast Saccharomyces cerevisiae and in mouse.^{[5] [6]}

Recombination during meiosis is often initiated by a DNA double-strand break (DSB) as illustrated in the accompanying diagram. During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule "invades" the DNA of a homologous chromosome that is not broken, forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and Homologous recombination). The pathway leading to a CO involves a double Holliday junction (DHJ) intermediate. Holliday junctions need to be resolved for CO recombination to be completed.

During meiosis in S. cerevisiae, transcription of the Exo1 gene is highly induced. In meiotic cells, Exo1 mutation reduces the processing of DSBs and the frequency of COs. Exo1 has two temporally and biochemically distinct functions in meiotic recombination.^[7] First, Exo1 acts as a 5’–3’ nuclease to resect DSB-ends. Later in the recombination process, Exo1 acts to facilitate the resolution of DHJs into COs, independently of its nuclease activities. In resolving DHJs, Exo 1 acts together with MLH1-MLH3 heterodimer (MutL gamma) and Sgs1 (ortholog of Bloom syndrome helicase) to define a joint molecule resolution pathway that produces the majority of crossovers.^[8]

Male mice deficient for Exo1 are capable of normal progress through the pachynema stage of meiosis, but most germ cells fail to progress normally to metaphase I due to dynamic loss of chiasmata. Surprisingly though, this meiotic role of Exo1 is not mediated by its nuclease activity per se, since Exo1-DA mice harboring a point mutation in Exo1's nuclease domain have no detectable meoitic defects. ^[9]

Interactions

Exonuclease 1 has been shown to interact with MSH2^{[2] [10] [11]} and MLH1.^[11]

Further reading

• Liberti SE, Rasmussen LJ . Is hEXO1 a cancer predisposing gene? . Mol. Cancer Res. . 2 . 8 . 427–32 . 2005 . 10.1158/1541-7786.427.2.8 . 15328369 . 9070659 . free .
• Holle GE . [Pathophysiology of ulcer disease] . Langenbecks Archiv für Chirurgie . 366 . 81–7 . 1985 . 2414623 . 10.1007/bf01836609. 19231591 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery. . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .
• Tishkoff DX, Amin NS, Viars CS . Identification of a human gene encoding a homologue of Saccharomyces cerevisiae EXO1, an exonuclease implicated in mismatch repair and recombination. . Cancer Res. . 58 . 22 . 5027–31 . 1998 . 9823303 . etal.
• Qiu J, Qian Y, Chen V . Human exonuclease 1 functionally complements its yeast homologues in DNA recombination, RNA primer removal, and mutation avoidance. . J. Biol. Chem. . 274 . 25 . 17893–900 . 1999 . 10364235 . 10.1074/jbc.274.25.17893 . etal. free .
• Lee BI, Wilson DM . The RAD2 domain of human exonuclease 1 exhibits 5' to 3' exonuclease and flap structure-specific endonuclease activities. . J. Biol. Chem. . 274 . 53 . 37763–9 . 2000 . 10608837 . 10.1074/jbc.274.53.37763 . free .
• Rasmussen LJ, Rasmussen M, Lee B . 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. . Mutat. Res. . 460 . 1 . 41–52 . 2000 . 10856833 . 10.1016/S0921-8777(00)00012-4. etal. 10.1.1.614.1507 .
• Wu Y, Berends MJ, Post JG . Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. . Gastroenterology . 120 . 7 . 1580–7 . 2001 . 11375940 . 10.1053/gast.2001.25117 . etal.
• Schmutte C, Sadoff MM, Shim KS . The interaction of DNA mismatch repair proteins with human exonuclease I. . J. Biol. Chem. . 276 . 35 . 33011–8 . 2001 . 11427529 . 10.1074/jbc.M102670200 . etal. free .
• Jäger AC, Rasmussen M, Bisgaard HC . HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes. . Oncogene . 20 . 27 . 3590–5 . 2001 . 11429708 . 10.1038/sj.onc.1204467 . 29870057 . etal.
• Genschel J, Bazemore LR, Modrich P . Human exonuclease I is required for 5' and 3' mismatch repair. . J. Biol. Chem. . 277 . 15 . 13302–11 . 2002 . 11809771 . 10.1074/jbc.M111854200 . free .
• Lee Bi BI, Nguyen LH, Barsky D . Molecular interactions of human Exo1 with DNA. . Nucleic Acids Res. . 30 . 4 . 942–9 . 2002 . 11842105 . 10.1093/nar/30.4.942 . 100345 . etal.
• Sun X, Zheng L, Shen B . Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome. . Cancer Res. . 62 . 21 . 6026–30 . 2002 . 12414623 .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . etal. 2002PNAS...9916899M . free .
• Jagmohan-Changur S, Poikonen T, Vilkki S . EXO1 variants occur commonly in normal population: evidence against a role in hereditary nonpolyposis colorectal cancer. . Cancer Res. . 63 . 1 . 154–8 . 2003 . 12517792 . etal.
• Sharma S, Sommers JA, Driscoll HC . 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. . J. Biol. Chem. . 278 . 26 . 23487–96 . 2003 . 12704184 . 10.1074/jbc.M212798200 . etal. free .
• Alam NA, Gorman P, Jaeger EE . Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability. . Cancer Genet. Cytogenet. . 147 . 2 . 121–7 . 2004 . 14623461 . 10.1016/S0165-4608(03)00196-1 . etal.
• Genschel J, Modrich P . Mechanism of 5'-directed excision in human mismatch repair. . Mol. Cell . 12 . 5 . 1077–86 . 2004 . 14636568 . 10.1016/S1097-2765(03)00428-3 . free .

Notes and References

1. ((Wilson DM III)), Carney JP, Coleman MA, Adamson AW, Christensen M, Lamerdin JE . Hex1: a new human Rad2 nuclease family member with homology to yeast exonuclease 1 . Nucleic Acids Res . 26 . 16 . 3762–8 . September 1998 . 9685493 . 147753 . 10.1093/nar/26.16.3762 .
2. Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J, Fishel R . Human exonuclease I interacts with the mismatch repair protein hMSH2 . Cancer Res . 58 . 20 . 4537–42 . November 1998 . 9788596 .
3. Web site: Entrez Gene: EXO1 exonuclease 1.
4. J. Biol. Chem. . Qiu J, Qian Y, Chen V, Guan MX, Shen B . Human exonuclease 1 functionally complements its yeast homologues in DNA recombination, RNA primer removal, and mutation avoidance. . June 1999 . 10364235 . 10.1074/jbc.274.25.17893 . 274 . 25 . 17893–900. free .
5. Tsubouchi H, Ogawa H . Exo1 roles for repair of DNA double-strand breaks and meiotic crossing over in Saccharomyces cerevisiae . Mol. Biol. Cell . 11 . 7 . 2221–33 . 2000 . 10888664 . 14915 . 10.1091/mbc.11.7.2221.
6. Wei K, Clark AB, Wong E, Kane MF, Mazur DJ, Parris T, Kolas NK, Russell R, Hou H, Kneitz B, Yang G, Kunkel TA, Kolodner RD, Cohen PE, Edelmann W . Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility . Genes Dev. . 17 . 5 . 603–14 . 2003 . 12629043 . 196005 . 10.1101/gad.1060603 .
7. Zakharyevich K, Ma Y, Tang S, Hwang PY, Boiteux S, Hunter N . Temporally and biochemically distinct activities of Exo1 during meiosis: double-strand break resection and resolution of double Holliday junctions . Mol. Cell . 40 . 6 . 1001–15 . 2010 . 21172664 . 3061447 . 10.1016/j.molcel.2010.11.032 .
8. Zakharyevich K, Tang S, Ma Y, Hunter N . Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase . Cell . 149 . 2 . 334–47 . 2012 . 22500800 . 3377385 . 10.1016/j.cell.2012.03.023 .
9. Wang S, Lee K, Gray S, Zhang Y, Tang C, Morrish RB, Tosti E, van Oers J, Amin MR, Cohen PE, MacCarthy T, Roa S, Scharff MD, Edelmann W, Chahwan R . Role of EXO1 nuclease activity in genome maintenance, the immune response and tumor suppression in Exo1D173A mice . Nucleic Acids Res . 50 . 14 . 8093–8106 . 2022 . 35849338 . 9371890 . 10.1093/nar/gkac616 .
10. Rasmussen . L J . Rasmussen M. Lee B. Rasmussen A K. Wilson D M. Nielsen F C. Bisgaard H C . June 2000 . 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 . Mutat. Res. . 460 . 1 . 41–52 . 0027-5107. 10856833 . 10.1016/S0921-8777(00)00012-4. 10.1.1.614.1507 .
11. Schmutte . C . Sadoff M M. Shim K S. Acharya S. Fishel R . August 2001 . The interaction of DNA mismatch repair proteins with human exonuclease I . J. Biol. Chem. . 276 . 35 . 33011–8 . 0021-9258. 11427529 . 10.1074/jbc.M102670200 . free .