Exonuclease 1

Last updated

EXO1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases EXO1 , HEX1, hExoI, exonuclease 1
External IDs OMIM: 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 Mb Chr 1: 175.71 – 175.74 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Contents

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

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. Homologous Recombination.jpg
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

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

Related Research Articles

<span class="mw-page-title-main">Chromosomal crossover</span> Cellular process

Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.

<span class="mw-page-title-main">Non-homologous end joining</span> Pathway that repairs double-strand breaks in DNA

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.

<span class="mw-page-title-main">DNA mismatch repair</span> System for fixing base errors of DNA replication

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

<span class="mw-page-title-main">Holliday junction</span> Branched nucleic acid structure

A Holliday junction is a branched nucleic acid structure that contains four double-stranded arms joined. These arms may adopt one of several conformations depending on buffer salt concentrations and the sequence of nucleobases closest to the junction. The structure is named after Robin Holliday, the molecular biologist who proposed its existence in 1964.

<span class="mw-page-title-main">MSH2</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.

<span class="mw-page-title-main">MLH1</span> Protein-coding gene in humans

DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

<span class="mw-page-title-main">MSH6</span> Protein-coding gene in the species Homo sapiens

MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6. The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair.

Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.

<span class="mw-page-title-main">MAP2K1</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.

<span class="mw-page-title-main">MRE11A</span> Protein-coding gene in the species Homo sapiens

Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the MRE11 gene. The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.

<span class="mw-page-title-main">Mismatch repair endonuclease PMS2</span> Protein-coding gene in the species Homo sapiens

Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.

<span class="mw-page-title-main">Bloom syndrome protein</span> Mammalian protein found in humans

Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.

<span class="mw-page-title-main">Rad50</span> Protein-coding gene in the species Homo sapiens

DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.

<span class="mw-page-title-main">RAD1 homolog</span> Protein-coding gene in the species Homo sapiens

Cell cycle checkpoint protein RAD1 is a protein that in humans is encoded by the RAD1 gene.

<span class="mw-page-title-main">MSH3</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein, MutS Homolog 3 (MSH3) is a human homologue of the bacterial mismatch repair protein MutS that participates in the mismatch repair (MMR) system. MSH3 typically forms the heterodimer MutSβ with MSH2 in order to correct long insertion/deletion loops and base-base mispairs in microsatellites during DNA synthesis. Deficient capacity for MMR is found in approximately 15% of colorectal cancers, and somatic mutations in the MSH3 gene can be found in nearly 50% of MMR-deficient colorectal cancers.

<span class="mw-page-title-main">PMS1</span> Protein-coding gene in humans

PMS1 protein homolog 1 is a protein that in humans is encoded by the PMS1 gene.

<span class="mw-page-title-main">MSH4</span> Protein-coding gene in the species Homo sapiens

MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene.

<span class="mw-page-title-main">REXO2</span> Protein-coding gene in humans

REX2, RNA exonuclease 2 homolog , also known as REXO2, is an enzyme which in humans is encoded by the REXO2 gene.

<span class="mw-page-title-main">MLH3</span> Protein-coding gene in humans

DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.

<span class="mw-page-title-main">RAD54B</span> Protein-coding gene in the species Homo sapiens

DNA repair and recombination protein RAD54B is a protein that in humans is encoded by the RAD54B gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000174371 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 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. 1 2 "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. 1 2 3 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. 1 2 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. 1 2 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.

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