Exonuclease 1


Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.
This gene encodes a protein with 5' to 3' exonuclease activity as well as an RNase H activity. 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.

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 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. After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover or a non-crossover recombinant. The pathway leading to a CO involves a double Holliday junction 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. 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 and Sgs1 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.

Interactions

Exonuclease 1 has been shown to interact with MSH2 and MLH1.