Resolution of Meiotic Holliday Junction

Stable Identifier
Reaction [omitted]
Mus musculus
SVG |   | PPTX  | SBGN
Resolution of Meiotic Holliday Junction
Meiotic Holliday junctions are cleaved to yield either crossovers or non-crossovers (gene conversions). The resolvase or resolvases responsible for cleavage are unknown but a resolvase complex in human cells may include SLX4 and/or GEN1.
Two classes of crossovers have been defined: class I crossovers are dependent on the MutL homologs, Mlh1 and Mlh3 as well as residual Msh4 and Msh5 (Baker et al. 1996, Anderson et al. 1999, Santucci-Darmanin et al. 2000, Lipkin et al. 2002, Moens et al. 2002, Marcon and Moens 2003, Kolas et al. 2005, de Boer et al. 2006, Moens et al. 2007, Svetlanov et al. 2008) while class II crossovers are dependent on the MUS81-EME1 endonuclease (Holloway et al. 2008).
Class I crossovers constitute 90-95% of all crossovers, and correspond to meiotic nodules that contain Mlh1and Mlh3. These arise as a subset of the many hundreds of Msh4/Msh5-positive meiotic nodules that arise at the time of double Holliday junction formation. What happens to all the other meiotic nodules is not clear, but they most likely follow a second pathway that results in non-crossovers (or gene conversions). Mlh1 and Mlh3 form heterodimers that bind mismatches in duplex DNA. In mouse Mlh1 is required for crossovers but not for non-crossover resolution of Holliday junctions. About 10% of early recombination nodules are somehow selected to become class I crossover events by losing Blm (and probably associated Top3a) and gaining Mlh1 and Mlh3.
The selection of sites for class II crossovers follows an, as yet, unknown pathway, but almost certainly stems from the same initiating D-loop intermediate.
In the process known as crossover interference, the presence of a crossover nodule inhibits formation of nearby crossover nodules so that crossovers are not clustered and each chromosome bivalent has at least one crossover. Crossover interference is seen among nodules at two stages: Rpa-containing nodules during late zygonema and Mlh1-containing nodules during pachynema (de Boer et al. 2006). Class II crossovers are not subject to interference constraints.
The checkpoint kinase Cdk2 colocalizes with Mlh1 and is required for synapsis and recombination, however its function is unknown (Ashley et al. 2001, Viera et al. 2009).
Literature References
PubMed ID Title Journal Year
8673133 Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over

Bradley, A, Christie, DM, Harris, AC, Baker, SM, Prolla, TA, Plug, AW, Arnheim, N, Monell, C, Yao, X, Ashley, T, Bronner, CE, Liskay, RM

Nat Genet 1996
17344431 Initiation and resolution of interhomolog connections: crossover and non-crossover sites along mouse synaptonemal complexes

Marcon, E, Kochakpour, N, Shore, JS, Moens, PB, Spyropoulos, B

J Cell Sci 2007
10928988 MSH4 acts in conjunction with MLH1 during mammalian meiosis

Desnuelle, C, Walpita, D, Lespinasse, F, Santucci-Darmanin, S, Paquis-Flucklinger, V, Ashley, T

FASEB J 2000
16260499 Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I

Lipkin, SM, Edelmann, W, Svetlanov, A, Kolas, NK, Lenzi, ML, Macaluso, FP, Greally, J, Cohen, PE, Liskay, RM

J Cell Biol 2005
18430927 Distinct functions of MLH3 at recombination hot spots in the mouse

de Massy, B, Baudat, F, Svetlanov, A, Cohen, PE

Genetics 2008
10101178 Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein

Anderson, LK, Reeves, A, Ashley, T, Webb, LM

Genetics 1999
14704203 MLH1p and MLH3p localize to precociously induced chiasmata of okadaic-acid-treated mouse spermatocytes

Moens, P, Marcon, E

Genetics 2003
11950880 The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination

Kolas, NK, Marcon, E, Cohen, PE, Moens, PB, Spyropoulos, B, Tarsounas, M

J Cell Sci 2002
19494131 CDK2 is required for proper homologous pairing, recombination and sex-body formation during male mouse meiosis

Barbero, JL, Suja, JA, Ortega, S, Rufas, JS, Martinez, I, Viera, A

J Cell Sci 2009
12091911 Meiotic arrest and aneuploidy in MLH3-deficient mice

Collins, FS, Lipkin, SM, Cheng, J, Cohen, PE, Shanmugarajah, D, Schwartzberg, P, Thomas, J, Wang, V, Lenzi, M, Gilgeous, A, Green, ED, Moens, PB, Touchman, JW

Nat Genet 2002
18787696 MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis

Holloway, JK, Edelmann, W, McGowan, CH, Cohen, PE, Booth, J

PLoS Genet 2008
11171374 Localization of two mammalian cyclin dependent kinases during mammalian meiosis

Walpita, D, de Rooij, DG, Ashley, T

J Cell Sci 2001
16766662 Two levels of interference in mouse meiotic recombination

de Boer, E, Heyting, C, Stam, P, Pastink, A, Dietrich, AJ

Proc Natl Acad Sci U S A 2006
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