Meiotic recombination (Homo sapiens)

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4, 17, 227, 9, 13106, 12, 15, 16, 29...2, 3, 8, 11, 16...271, 3, 8, 11, 16...5, 14, 16, 25, 26SPO11 Dimer Meiotic Single-stranded DNA Complex Nucleosome containing Histone gamma-H2A.x MSH4MSH5 Heterodimer SPO11 Dimer SPO11 Dimer Nucleosome containing Histone H2A.x RPA heterotrimer Nucleosome with Histone H3 Trimethylated at Lysine-4 RPA heterotrimer MRE11RAD50NBS1 complex SPO11 Covalently Attached to Oligonucleotide Meiotic Holliday Junction Nucleosome with Histone H3 Dimethylated at Lysine-4 RPA heterotrimer Nucleosome containing Histone gamma-H2A.x RPA heterotrimer MRNCtIP Complex MLH1MLH3 Heterodimer Cleaved Meiotic Holliday Junction SPO11 Covalently Attached to Double-strand Break nucleoplasmMeiotic D-loop Complex HOP2PRDM9DNA Complex HIST1H4A ATM SPO11 DimerCDK2 BRCA1 CDK4PRDM9 HIST1H4A BLM BRCA2 HIST3H3 Nucleosome with Histone H3 Dimethylated at Lysine-4RAD50 MSH5 RPA1 RPA2 PRDM9DMC1 TOP3ASPO11 HIST1H4A HIST3H3 HIST1H4A Cleaved Meiotic Holliday JunctionSPO11 Covalently Attached to OligonucleotideMLH1MND1 RAD51 CDK2BRCA2MSH4 BRCA2 BRCA1HIST3H3 AdoMetDNAp-S139-H2AFX DMC1 PRDM9DNA ComplexATM SPO11 RPA1 Meiotic Single-stranded DNA ComplexRAD51 BLMRPA2 3' overhanging DNA at resected DSB endsRPA1 HOP2MLH3 RPA2 RAD51CATM SPO11 Covalently Attached to Double-strand BreakDMC1NBN CDK4MLH1 MLH3DNAAdoHcyNucleosome with Histone H3 Trimethylated at Lysine-4Meiotic Holliday JunctionMSH4ATMRPA3 SPO11 RBBP8 RPA3 RPA1 RPA3 RPA3 HIST1H4A TOP3A ATM Nucleosome containing Histone H2A.xp-S139-H2AFX RAD51PSMC3IP Meiotic D-loop ComplexTEX15CDK4RPA heterotrimerMSH5MRE11A H2AFX CDK4BRCA2 RPA2 MRNCtIP Complex30277


Description

Meiotic recombination exchanges segments of duplex DNA between chromosomal homologs, generating genetic diversity (reviewed in Handel and Schimenti 2010, Inagaki et al. 2010, Cohen et al. 2006). There are two forms of recombination: non-crossover (NCO) and crossover (CO). In mammals, the former is required for correct pairing and synapsis of homologous chromosomes, while CO intermediates called chiasmata are required for correct segregation of bivalents.
Meiotic recombination is initiated by double-strand breaks created by SPO11, which remains covalently attached to the 5' ends after cleavage. SPO11 is removed by cleavage of single DNA strands adjacent to the covalent linkage. The resulting 5' ends are further resected to produce protruding 3' ends. The single-stranded 3' ends are bound by RAD51 and DMC1, homologs of RecA that catalyze a search for homology between the bound single strand and duplex DNA of the chromosomal homolog. RAD51 and DMC1 then catalyze the invasion of the single strand into the homologous duplex and the formation of a D-loop heteroduplex. Approximately 90% of heteroduplexes are resolved without crossovers (NCO), probably by synthesis-dependent strand annealing.
The invasive strand is extended along the homolog and ligated back to its original duplex, creating a double Holliday junction. The mismatch repair proteins MSH4, MSH5 participate in this process, possibly by stabilizing the duplexes. The mismatch repair proteins MLH1 and MLH3 are then recruited to the double Holliday structure and an unidentified resolvase (Mus81? Gen1?) cleaves the junctions to yield a crossover.
Crossovers are not randomly distributed: The histone methyltransferase PRDM9 recruits the recombination machinery to genetically determined hotspots in the genome and each incipient crossover somehow inhibits formation of crossovers nearby, a phenomenon called crossover interference. Each chromosome bivalent, including the X-Y body in males, has at least one crossover and this is required for meiosis to proceed correctly. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=912446

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Bibliography

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  2. Masson JY, Davies AA, Hajibagheri N, Van Dyck E, Benson FE, Stasiak AZ, Stasiak A, West SC.; ''The meiosis-specific recombinase hDmc1 forms ring structures and interacts with hRad51.''; PubMed Europe PMC Scholia
  3. Murayama Y, Kurokawa Y, Mayanagi K, Iwasaki H.; ''Formation and branch migration of Holliday junctions mediated by eukaryotic recombinases.''; PubMed Europe PMC Scholia
  4. Oliver-Bonet M, Turek PJ, Sun F, Ko E, Martin RH.; ''Temporal progression of recombination in human males.''; PubMed Europe PMC Scholia
  5. Okorokov AL, Chaban YL, Bugreev DV, Hodgkinson J, Mazin AV, Orlova EV.; ''Structure of the hDmc1-ssDNA filament reveals the principles of its architecture.''; PubMed Europe PMC Scholia
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  7. Hayashi K, Yoshida K, Matsui Y.; ''A histone H3 methyltransferase controls epigenetic events required for meiotic prophase.''; PubMed Europe PMC Scholia
  8. Oliver-Bonet M, Campillo M, Turek PJ, Ko E, Martin RH.; ''Analysis of replication protein A (RPA) in human spermatogenesis.''; PubMed Europe PMC Scholia
  9. Snowden T, Acharya S, Butz C, Berardini M, Fishel R.; ''hMSH4-hMSH5 recognizes Holliday Junctions and forms a meiosis-specific sliding clamp that embraces homologous chromosomes.''; PubMed Europe PMC Scholia
  10. Snowden T, Shim KS, Schmutte C, Acharya S, Fishel R.; ''hMSH4-hMSH5 adenosine nucleotide processing and interactions with homologous recombination machinery.''; PubMed Europe PMC Scholia
  11. Barlow AL, Hultén MA.; ''Crossing over analysis at pachytene in man.''; PubMed Europe PMC Scholia
  12. Sheridan SD, Yu X, Roth R, Heuser JE, Sehorn MG, Sung P, Egelman EH, Bishop DK.; ''A comparative analysis of Dmc1 and Rad51 nucleoprotein filaments.''; PubMed Europe PMC Scholia
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  14. Berg IL, Neumann R, Lam KW, Sarbajna S, Odenthal-Hesse L, May CA, Jeffreys AJ.; ''PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans.''; PubMed Europe PMC Scholia
  15. Cohen PE, Pollack SE, Pollard JW.; ''Genetic analysis of chromosome pairing, recombination, and cell cycle control during first meiotic prophase in mammals.''; PubMed Europe PMC Scholia
  16. Baumann P, West SC.; ''Heteroduplex formation by human Rad51 protein: effects of DNA end-structure, hRP-A and hRad52.''; PubMed Europe PMC Scholia
  17. Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID.; ''The Bloom's syndrome gene product interacts with topoisomerase III.''; PubMed Europe PMC Scholia
  18. Handel MA, Schimenti JC.; ''Genetics of mammalian meiosis: regulation, dynamics and impact on fertility.''; PubMed Europe PMC Scholia
  19. Sehorn MG, Sigurdsson S, Bussen W, Unger VM, Sung P.; ''Human meiotic recombinase Dmc1 promotes ATP-dependent homologous DNA strand exchange.''; PubMed Europe PMC Scholia
  20. Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, Coop G, de Massy B.; ''PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice.''; PubMed Europe PMC Scholia
  21. Cannavo E, Marra G, Sabates-Bellver J, Menigatti M, Lipkin SM, Fischer F, Cejka P, Jiricny J.; ''Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair.''; PubMed Europe PMC Scholia
  22. Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS, McVean G, Donnelly P.; ''Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination.''; PubMed Europe PMC Scholia
  23. Baumann P, Benson FE, West SC.; ''Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro.''; PubMed Europe PMC Scholia
  24. Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J, Jackson SP.; ''Human CtIP promotes DNA end resection.''; PubMed Europe PMC Scholia
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  26. Thorslund T, Esashi F, West SC.; ''Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1.''; PubMed Europe PMC Scholia
  27. Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM.; ''Association of BRCA1 with Rad51 in mitotic and meiotic cells.''; PubMed Europe PMC Scholia
  28. Inagaki A, Schoenmakers S, Baarends WM.; ''DNA double strand break repair, chromosome synapsis and transcriptional silencing in meiosis.''; PubMed Europe PMC Scholia
  29. Enomoto R, Kinebuchi T, Sato M, Yagi H, Kurumizaka H, Yokoyama S.; ''Stimulation of DNA strand exchange by the human TBPIP/Hop2-Mnd1 complex.''; PubMed Europe PMC Scholia
  30. Barlow AL, Benson FE, West SC, Hultén MA.; ''Distribution of the Rad51 recombinase in human and mouse spermatocytes.''; PubMed Europe PMC Scholia
  31. Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R.; ''hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis.''; PubMed Europe PMC Scholia
  32. Golub EI, Gupta RC, Haaf T, Wold MS, Radding CM.; ''Interaction of human rad51 recombination protein with single-stranded DNA binding protein, RPA.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115022view16:55, 25 January 2021ReactomeTeamReactome version 75
113467view11:54, 2 November 2020ReactomeTeamReactome version 74
112666view16:05, 9 October 2020ReactomeTeamReactome version 73
101583view11:44, 1 November 2018ReactomeTeamreactome version 66
101119view21:29, 31 October 2018ReactomeTeamreactome version 65
100647view20:03, 31 October 2018ReactomeTeamreactome version 64
100197view16:47, 31 October 2018ReactomeTeamreactome version 63
99748view15:13, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93776view13:35, 16 August 2017ReactomeTeamreactome version 61
93304view11:19, 9 August 2017ReactomeTeamreactome version 61
87986view13:23, 25 July 2016RyanmillerOntology Term : 'cell cycle pathway, meiotic' added !
87881view12:18, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86388view09:16, 11 July 2016ReactomeTeamreactome version 56
83114view10:00, 18 November 2015ReactomeTeamVersion54
81755view09:56, 26 August 2015ReactomeTeamVersion53
76904view08:17, 17 July 2014ReactomeTeamFixed remaining interactions
76609view11:58, 16 July 2014ReactomeTeamFixed remaining interactions
75940view09:59, 11 June 2014ReactomeTeamRe-fixing comment source
75643view10:53, 10 June 2014ReactomeTeamReactome 48 Update
74998view13:51, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74642view08:42, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
3' overhanging DNA at resected DSB endsREACT_5086 (Reactome)
ATM ProteinQ13315 (Uniprot-TrEMBL)
ATMProteinQ13315 (Uniprot-TrEMBL)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BLM ProteinP54132 (Uniprot-TrEMBL)
BLMProteinP54132 (Uniprot-TrEMBL)
BRCA1 ProteinP38398 (Uniprot-TrEMBL)
BRCA1ProteinP38398 (Uniprot-TrEMBL)
BRCA2 ProteinP51587 (Uniprot-TrEMBL)
BRCA2ProteinP51587 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK2ProteinP24941 (Uniprot-TrEMBL)
CDK4ProteinP11802 (Uniprot-TrEMBL)
Cleaved Meiotic Holliday JunctionComplexREACT_27914 (Reactome)
DMC1 ProteinQ14565 (Uniprot-TrEMBL)
DMC1ProteinQ14565 (Uniprot-TrEMBL)
DNAREACT_3913 (Reactome)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
HIST1H4A ProteinP62805 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
HOP2ComplexREACT_27766 (Reactome)
MLH1 ProteinP40692 (Uniprot-TrEMBL)
MLH1ProteinP40692 (Uniprot-TrEMBL)
MLH3 ProteinQ9UHC1 (Uniprot-TrEMBL)
MLH3ProteinQ9UHC1 (Uniprot-TrEMBL)
MND1 ProteinQ9BWT6 (Uniprot-TrEMBL)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRN CtIP ComplexComplexREACT_27850 (Reactome)
MSH4 ProteinO15457 (Uniprot-TrEMBL)
MSH4ProteinO15457 (Uniprot-TrEMBL)
MSH5 ProteinO43196 (Uniprot-TrEMBL)
MSH5ProteinO43196 (Uniprot-TrEMBL)
Meiotic D-loop ComplexComplexREACT_27539 (Reactome)
Meiotic Holliday JunctionComplexREACT_27566 (Reactome)
Meiotic Single-stranded DNA ComplexComplexREACT_27879 (Reactome)
NBN ProteinO60934 (Uniprot-TrEMBL)
Nucleosome containing Histone H2A.xComplexREACT_27840 (Reactome)
Nucleosome with Histone H3 Dimethylated at Lysine-4ComplexREACT_27650 (Reactome)
Nucleosome with Histone H3 Trimethylated at Lysine-4ComplexREACT_27602 (Reactome)
PRDM9 DNA ComplexComplexREACT_27470 (Reactome)
PRDM9 ProteinQ9NQV7 (Uniprot-TrEMBL)
PRDM9ProteinQ9NQV7 (Uniprot-TrEMBL)
PSMC3IP ProteinQ9P2W1 (Uniprot-TrEMBL)
RAD50 ProteinQ92878 (Uniprot-TrEMBL)
RAD51 ProteinQ06609 (Uniprot-TrEMBL)
RAD51CProteinO43502 (Uniprot-TrEMBL)
RAD51ProteinQ06609 (Uniprot-TrEMBL)
RBBP8 ProteinQ99708 (Uniprot-TrEMBL)
RPA heterotrimerComplexREACT_3427 (Reactome)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
SPO11 Covalently Attached to Double-strand BreakComplexREACT_27482 (Reactome) The gene encoding SPO11 shares sequence similarity to TopoVI, a type II topoisomerase. SPO11 dimers cleave both strands of DNA. Each subunit of the dimer remains covalently attached to the 5' end of one strand of DNA via a phosphodiester linkage to a conserved tyrosine residue of SPO11. In addition to SPO11, work from budding yeast has shown a total of 7 proteins essential for double strand break formation. The mammalian ortholog of Mei4 (S. cerevisiae) as well as a mammalian-specific gene called Mei1 are essential to formation of meiotic double strand breaks.
SPO11 Covalently Attached to OligonucleotideComplexREACT_27423 (Reactome)
SPO11 DimerComplexREACT_27627 (Reactome)
SPO11 ProteinQ9Y5K1 (Uniprot-TrEMBL)
TEX15ProteinQ9BXT5 (Uniprot-TrEMBL)
TOP3A ProteinQ13472 (Uniprot-TrEMBL)
TOP3AProteinQ13472 (Uniprot-TrEMBL)
p-S139-H2AFX ProteinP16104 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
3' overhanging DNA at resected DSB endsArrowREACT_27209 (Reactome)
3' overhanging DNA at resected DSB endsREACT_27160 (Reactome)
ATMREACT_27160 (Reactome)
AdoHcyArrowREACT_27242 (Reactome)
AdoMetREACT_27242 (Reactome)
BLMArrowREACT_27206 (Reactome)
BLMREACT_27234 (Reactome)
BRCA1REACT_27160 (Reactome)
BRCA2ArrowREACT_27206 (Reactome)
BRCA2REACT_27160 (Reactome)
CDK2REACT_27206 (Reactome)
CDK4ArrowREACT_27206 (Reactome)
CDK4REACT_27160 (Reactome)
Cleaved Meiotic Holliday JunctionArrowREACT_27206 (Reactome)
DMC1ArrowREACT_27234 (Reactome)
DMC1REACT_27160 (Reactome)
DNAREACT_27239 (Reactome)
DNAREACT_27253 (Reactome)
DNAREACT_27300 (Reactome)
HOP2ArrowREACT_27300 (Reactome)
MLH1REACT_27206 (Reactome)
MLH3REACT_27206 (Reactome)
MRN CtIP ComplexREACT_27209 (Reactome)
MSH4ArrowREACT_27206 (Reactome)
MSH4REACT_27234 (Reactome)
MSH5ArrowREACT_27206 (Reactome)
MSH5REACT_27234 (Reactome)
Meiotic D-loop ComplexREACT_27234 (Reactome)
Meiotic Holliday JunctionArrowREACT_27234 (Reactome)
Meiotic Holliday JunctionREACT_27206 (Reactome)
Meiotic Single-stranded DNA ComplexREACT_27300 (Reactome)
Nucleosome containing Histone H2A.xREACT_27160 (Reactome)
Nucleosome with Histone H3 Dimethylated at Lysine-4REACT_27242 (Reactome)
Nucleosome with Histone H3 Trimethylated at Lysine-4ArrowREACT_27242 (Reactome)
PRDM9 DNA ComplexREACT_27242 (Reactome)
PRDM9REACT_27253 (Reactome)
RAD51ArrowREACT_27234 (Reactome)
RAD51CArrowREACT_27160 (Reactome)
RAD51REACT_27160 (Reactome)
REACT_27160 (Reactome) Two RecA homologs, RAD51 and the meiosis-specific DMC1, coat single-stranded 3' ends of DNA produced by resection of double-strand breaks (Barlow et al. 1997, Masson et al. 1999, Sehorn et al. 2004, Sheridan et al. 2008, Okorokov et al. 2010). RAD51 and DMC1 interact and colocalize to the same early recombination nodules (Masson et al. 1999). Knockouts of DMC1 abolish recombination and synapsis therefore RAD51 is not sufficient for recombination.
Immunocytology shows the RPA heterotrimer arrives at recombination nodules with or after RAD51 and DMC1 (Golub et al. 1999, Oliver-Bonet et al. 2005, Oliver-Bonet et al. 2007)). (In mitotic recombination RPA precedes RAD51.)
BRCA1 and BRCA2 are found extensively distributed on synaptonemal complexes. Results from human cells and knockout mice indicate that BRCA2, RAD51C, and TEX15 participate in loading RAD51 and DMC1 onto single-stranded DNA (Thorslund et al. 2007). BRCA1 participates in loading RAD51 but not DMC1 (Scully et al. 1997).
The kinase ATM is also localized to double-strand breaks where it phosphorylates histone H2AX.
In human spermatocytes about 350 early recombination nodules form but only about 10% will continue on to make crossovers. The remaining 90% are believed to be resolved by synthesis-dependent strand annealing, which transfers short segments of DNA (about 0.2-2.0 kilobases) between homologs.
REACT_27206 (Reactome) 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 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, while class II crossovers are dependent on the MUS81-EME1 endonuclease. 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 repair mismatches in duplex DNA. In mouse, MLH1 is required for crossovers but not for non?crossover resolution of Holliday junctions. About 10% of early meiotic nodules are somehow selected to become Class I crossover events, possibly by first losing BLM (and probably associated TOP3A), and acquiring 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. In mouse, crossover interference is seen among nodules at two stages: RPA?containing nodules during late zygonema and MLH1?containing nodules during pachynema. Class II crossovers are not subject to interference constraints.
REACT_27209 (Reactome) SPO11 forms a dimer and each subunit cleaves a single strand of DNA, thus creating a double-strand break. After cleaving DNA, a SPO11 subunit remains covalently attached to each 5' end via a tyrosine residue. SPO11 is removed from the DNA by cleavage of single strands 3' to the attached SPO11. The products are a resected 5' end (protruding 3' overhang) and a covalent complex of SPO11 with an oligonucleotide. Two size classes of oligonucleotide are observed: 12 to 26 nucleotides and 28 to 34 nucleotides. The enzyme responsible for excision of SPO11:oligonucleotide in mammals is inferred to be MRE11 in the MRE11:RAD50:NBS1:CtIP complex based on conservation of the reaction mechanism across yeast, plants, and animals (Sartori et al. 2007).
In fission and budding yeast the Mre11:Rad50:Xrs2/Nbs1 (MRN/MRX) complex is required for removal of SPO11. In human somatic cells the MRN complex together with CtIP resects double-strand breaks in somatic cells but the role of the MRN complex in mammalian meiosis, though essential, is unclear (Sartori et al. 2007).
After excision of SPO11:oligonucleotide the recessed 5' end is further resected by unknown exonucleases.
REACT_27234 (Reactome) The 3' end of the invading strand is extended by an unknown DNA polymerase and the extended strand is then ligated back to the original homolog, generating a double Holliday junction. MSH4 and MSH5 form heterodimers which bind Holliday junctions and, in the presence of ATP, slide along the parental duplexes (Bocker et al. 1999, Snowden et al. 2004, Snowden et al. 2008). MSH4 is present at hundreds of meiotic nodules during late zygotene but only about 10% of these nodules become crossovers (Oliver-Bonet et al. 2005). Bloom Syndrome protein (BLM) and Topoisomerase IIIa (TOP3A) are also present and may promote homologous recombination repair without crossing over (Johnson et al. 2000, Wu et al. 2000).
REACT_27239 (Reactome) The gene encoding SPO11 shares sequence similarity to TopoVI, a type II topoisomerase. SPO11 dimers cleave both strands of DNA. Each subunit of the dimer remains covalently attached to the 5' end of one strand of DNA via a phosphodiester linkage to a conserved tyrosine residue of SPO11. In addition to SPO11, work from budding yeast has shown a total of 7 proteins essential for double strand break formation. The mammalian ortholog of Mei4 (S. cerevisiae) as well as a mammalian-specific gene called Mei1 are essential to formation of meiotic double strand breaks.
REACT_27242 (Reactome) As inferred from experiments in vitro with mouse Prdm9, human PRDM9 methylates histone H3 dimethylated at lysine-4 to yield histone H3 trimethylated at lysine-4.
REACT_27253 (Reactome) PR-domain containing 9 (PRDM9) protein is a meiosis specific histone H3 lysine 4 (H3K4) methyltransferase, with a zinc finger domain at the C-terminus. Meiotic recombination hotspots in humans and mice are known to be sites for histone modification. PRDM9 has been shown to affect recombination profiles and meiotic recombination hotspot activity, by binding specific sequence motifs within or close to recombination hotspots (Baudat et al. 2010, Myers et al. 2010), and reorganizing chromatin structure. Variation within this protein has been proven to negatively affect human male fertility, with certain patients harboring variants at the PRDM9 locus exhibiting azoospermia. PRDM9 recognizes a specific sequence motif, but also acts at human hotspots lacking the motif, suggesting it is capable of acting in cis to regulate hotspot activity.
These specific sequence motifs also appear to be species specific, as the degenerate 13-bp motif associated with 40% of human hotspots does not function in chimpanzees, probably as a result of the rapidly evolving zinc finger domain (Myers et al. 2010). Subtle changes in the zinc finger array in humans can have global effects on recombination throughout the human genome, enhancing or decreasing the activity of a hotspot, or even creating entirely new hotspots (Berg et al. 2010). In addition to its role in regulating recombination hotspot activity, PRDM9 also appears to have a role in maintaining stability within the human genome, as variation in the PRDM9 gene can lead to large-scale genomic rearrangements and minisatellite instability in humans.
REACT_27300 (Reactome) Following double strand break (DSB) formation and strand resection, RAD51 and DMC1 coat single-stranded 3' ends of DNA and catalyze the search for homology and strand invasion into the DNA duplex of the chromosomal homolog (Baumann et al. 1996, Barlow et al. 1997, Benson et al. 1998, Baumann and West 1999, Masson et al. 1999, Sehorn et al. 2004, Murayama et al. 2008). The invading strand displaces the original strand of the chromosomal homolog creating a D-loop structure. Other proteins present in the complex are inferred from cytology (Barlow et al. 1997, Oliver-Bonet et al. 2005, Oliver-Bonet et al. 2007).
RPA heterotrimerArrowREACT_27206 (Reactome)
RPA heterotrimerREACT_27160 (Reactome)
SPO11 Covalently Attached to OligonucleotideArrowREACT_27209 (Reactome)
SPO11 DimerREACT_27239 (Reactome)
TEX15ArrowREACT_27160 (Reactome)
TOP3AArrowREACT_27206 (Reactome)
TOP3AREACT_27234 (Reactome)
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