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Exonuclease 1

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EXO1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesEXO1, HEX1, hExoI, exonuclease 1
External IDsOMIM: 606063; MGI: 1349427; HomoloGene: 31352; GeneCards: EXO1; OMA:EXO1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9156

26909

Ensembl

ENSG00000174371

ENSMUSG00000039748

UniProt

Q9UQ84
Q5T397

Q9QZ11

RefSeq (mRNA)

NM_003686
NM_006027
NM_130398
NM_001319224

NM_012012

RefSeq (protein)

NP_001306153
NP_003677
NP_006018
NP_569082

NP_036142

Location (UCSC)Chr 1: 241.85 – 241.9 MbChr 1: 175.71 – 175.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.[5][6][7]

This gene encodes a protein with 5' to 3' exonuclease activity as well as RNase activity (endonuclease activity cleaving RNA on DNA/RNA hybrid).[8] 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.[7]

Meiosis

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A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

ExoI is essential for meiotic progression through metaphase I in the budding yeast Saccharomyces cerevisiae and in mouse.[9][10]

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.[9] In meiotic cells, Exo1 mutation reduces the processing of DSBs and the frequency of COs.[9] Exo1 has two temporally and biochemically distinct functions in meiotic recombination.[11] 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.[12]

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.[10] 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. [13]

Interactions

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Exonuclease 1 has been shown to interact with MSH2[6][14][15] and MLH1.[15]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000174371 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000039748 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Wilson DM III, Carney JP, Coleman MA, Adamson AW, Christensen M, Lamerdin JE (September 1998). "Hex1: a new human Rad2 nuclease family member with homology to yeast exonuclease 1". Nucleic Acids Res. 26 (16): 3762–8. doi:10.1093/nar/26.16.3762. PMC 147753. PMID 9685493.
  6. ^ a b Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J, Fishel R (November 1998). "Human exonuclease I interacts with the mismatch repair protein hMSH2". Cancer Res. 58 (20): 4537–42. PMID 9788596.
  7. ^ a b "Entrez Gene: EXO1 exonuclease 1".
  8. ^ Qiu J, Qian Y, Chen V, Guan MX, Shen B (June 1999). "Human exonuclease 1 functionally complements its yeast homologues in DNA recombination, RNA primer removal, and mutation avoidance". J. Biol. Chem. 274 (25): 17893–900. doi:10.1074/jbc.274.25.17893. PMID 10364235.
  9. ^ a b c Tsubouchi H, Ogawa H (2000). "Exo1 roles for repair of DNA double-strand breaks and meiotic crossing over in Saccharomyces cerevisiae". Mol. Biol. Cell. 11 (7): 2221–33. doi:10.1091/mbc.11.7.2221. PMC 14915. PMID 10888664.
  10. ^ a b 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 (2003). "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. doi:10.1101/gad.1060603. PMC 196005. PMID 12629043.
  11. ^ Zakharyevich K, Ma Y, Tang S, Hwang PY, Boiteux S, Hunter N (2010). "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. doi:10.1016/j.molcel.2010.11.032. PMC 3061447. PMID 21172664.
  12. ^ Zakharyevich K, Tang S, Ma Y, Hunter N (2012). "Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase". Cell. 149 (2): 334–47. doi:10.1016/j.cell.2012.03.023. PMC 3377385. PMID 22500800.
  13. ^ 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 (2022). "Role of EXO1 nuclease activity in genome maintenance, the immune response and tumor suppression in Exo1D173A mice". Nucleic Acids Res. 50 (14): 8093–8106. doi:10.1093/nar/gkac616. PMC 9371890. PMID 35849338.
  14. ^ Rasmussen LJ, 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. CiteSeerX 10.1.1.614.1507. doi:10.1016/S0921-8777(00)00012-4. ISSN 0027-5107. PMID 10856833.
  15. ^ a b 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. doi:10.1074/jbc.M102670200. ISSN 0021-9258. PMID 11427529.

Further reading

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