Exonuclease 1 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that in humans is encoded by the ''EXO1''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
This gene encodes a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
with 5' to 3'
exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is t ...
activity as well as
RNase
Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within th ...
activity (endonuclease activity cleaving RNA on DNA/RNA hybrid).
It is similar to the Saccharomyces cerevisiae protein Exo1 which interacts with Msh2 and which is involved in
DNA mismatch repair
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.
Mismatch ...
and
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
. Alternative splicing of this gene results in three transcript variants encoding two different isoforms.
Meiosis
ExoI is essential for meiotic progression through metaphase I in the budding yeast ''Saccharomyces cerevisiae'' and in mouse.
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
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points along ...
that is not broken, forming a
displacement loop
In molecular biology, a displacement loop or D-loop is a DNA structure where the two strands of a double-stranded DNA molecule are separated for a stretch and held apart by a third strand of DNA. An R-loop is similar to a D-loop, but in this ca ...
(
D-loop
In molecular biology, a displacement loop or D-loop is a DNA structure where the two strands of a double-stranded DNA molecule are separated for a stretch and held apart by a third strand of DNA. An R-loop is similar to a D-loop, but in this cas ...
). 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
Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukary ...
and
Homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
). The pathway leading to a CO involves a double
Holliday junction
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 ...
(DHJ) intermediate. Holliday junctions need to be resolved for CO recombination to be completed.
During
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately ...
in ''S. cerevisiae'',
transcription of the Exo1 gene is highly induced.
In meiotic cells, Exo1
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
reduces the processing of DSBs and the frequency of COs.
Exo1 has two temporally and biochemically distinct functions in meiotic recombination.
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
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. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 ...
-
MLH3
DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the ''MLH3'' gene.
Function
This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic in ...
heterodimer (MutL gamma) and
Sgs1
Sgs1, also known as slow growth suppressor 1, is a DNA helicase protein found in ''Saccharomyces cerevisiae''. It is a homolog of the bacterial RecQ helicase. Like the other members of the RecQ helicase family, Sgs1 is important for DNA repair ...
(ortholog of
Bloom syndrome helicase) to define a joint molecule resolution pathway that produces the majority of crossovers.
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.
Interactions
Exonuclease 1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizat ...
with
MSH2
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 code ...
and MLH1
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. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 ...
.[
]
References
Further reading
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