Meiotic recombination (Homo sapiens)

From WikiPathways

Jump to: navigation, search
5, 23, 326, 7, 9, 12, 14...153, 11, 14, 16, 18...30151, 19, 294, 10, 14, 24, 262, 8, 9, 12, 14...nucleoplasmH2AFJ SPO11 MLH3 MLH1 HIST1H2BD ATM HIST1H2BN p-S140-H2AFX HIST1H2BA HIST1H4 HIST1H2BA BLMTOP3AHIST1H2BL HIST1H2BB BRCA2 HIST2H2BE HIST1H2BK HIST1H2BC HIST1H2BH H2AFX DNA double-strand break ends HIST2H2AA3 Nucleosome withH3K4me3MRN:CtIPMe3K5-HIST1H3A HIST1H2AJ HIST1H2AD MLH13' overhanging DNAat resected DSBendsRAD51CRBBP8 BRCA2Me2K5-H3F3A Meioticsingle-stranded DNAcomplexHIST2H2BE DNA DNA double-strand break ends with 3' single-strand breaks Heteroduplex DNA containing D-loop structure HIST1H2BJ HIST1H2BH HIST1H2BO HIST1H2BO MND1 MSH5HIST1H2BB 3' overhanging DNA at resected DSB ends CDK2NBN H2AFV BRCA1 BLM RPA2 PRDM9:DNAHIST1H4 HIST3H2BB SPO11 DimerTOP3A HIST1H2BD HIST1H4 HIST1H2BM HIST1H2BL HIST1H2BA RPA heterotrimerCDK4 HIST2H2BE HIST3H3 H2BFS HIST1H2BB ATMHIST1H2BD HIST1H2AB HIST1H2AD Cleaved MeioticHolliday JunctionH2AFX-NucleosomeHIST1H2AC HIST3H3 AdoHcyHIST1H2BN H2AFB1 HIST1H2BM SPO11 H2AFV Me2K5-HIST1H3A HIST1H2AJ HIST1H2BJ Me3K5-H3F3A ATM SPO11 H2AFZ BRCA1RPA1 CDK4RPA3 HIST3H3 CDK4 Me3K5-HIST2H3A H2AFB1 Meiotic HollidayJunctionAdoMetHIST3H2BB MRE11A HIST1H2BJ HIST1H2BH p-S140-H2AFX Meiotic D-loopcomplexHIST1H2BL HIST1H2BA HIST1H2BC CDK4 ATM MSH5 HIST1H2BK Nucleosome withH3K4me2HIST2H2BE HIST3H2BB HIST3H2BB H2BFS BRCA2 HIST1H4 RAD51 SPO11:oligonucleotideHOP2(TBPIP):MND1RAD51HIST1H2BN HIST1H2BJ RPA3 H2AFZ PRDM9 DMC1 HIST1H2BN HIST1H2BJ HIST1H2BC HIST1H2BK DNAMe2K5-HIST2H3A HIST1H2BD DMC1 HIST1H2BA cleaved Holliday structure HIST1H2BM RPA1 Holliday structure HIST2H2BE RPA3 HIST1H2BK DMC1HIST3H2BB HIST1H2BO RPA2 PRDM9RAD50 PSMC3IP DNAH2BFS MSH4 RPA1 HIST1H2BH HIST1H2BN RPA2 SPO11 HIST1H2BM TEX15RPA2 H2BFS ATM HIST1H2BO RAD51 SPO11:double standbreakH2AFX HIST1H2BD CDK2 MSH4RPA1 HIST2H2AC HIST1H2BL HIST1H2BB HIST2H2AA3 HIST1H2BC HIST1H2BM HIST1H2BH HIST2H2AC HIST1H2BB H2BFS BRCA2 H2AFJ HIST1H2BK HIST1H2BO HIST1H2AB MLH3H2AFX Single-Stranded Oligodeoxyribonucleotide (12 to 34 nucleotides) HIST1H4 SPO11:double strandbreak with 3'single strandbreaksRPA3 HIST1H2BC HIST1H2BL HIST1H2AC 15113


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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 912446
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. 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
  2. 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
  3. Johnson FB, Lombard DB, Neff NF, Mastrangelo MA, Dewolf W, Ellis NA, Marciniak RA, Yin Y, Jaenisch R, Guarente L.; ''Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells.''; PubMed Europe PMC
  4. Kondo E, Horii A, Fukushige S.; ''The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2.''; PubMed Europe PMC
  5. 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
  6. Baumann P, West SC.; ''Heteroduplex formation by human Rad51 protein: effects of DNA end-structure, hRP-A and hRad52.''; PubMed Europe PMC
  7. Murayama Y, Kurokawa Y, Mayanagi K, Iwasaki H.; ''Formation and branch migration of Holliday junctions mediated by eukaryotic recombinases.''; PubMed Europe PMC
  8. 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
  9. Barlow AL, Benson FE, West SC, Hultén MA.; ''Distribution of the Rad51 recombinase in human and mouse spermatocytes.''; PubMed Europe PMC
  10. Santucci-Darmanin S, Walpita D, Lespinasse F, Desnuelle C, Ashley T, Paquis-Flucklinger V.; ''MSH4 acts in conjunction with MLH1 during mammalian meiosis.''; PubMed Europe PMC
  11. 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
  12. 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
  13. 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
  14. Oliver-Bonet M, Turek PJ, Sun F, Ko E, Martin RH.; ''Temporal progression of recombination in human males.''; PubMed Europe PMC
  15. 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
  16. Snowden T, Shim KS, Schmutte C, Acharya S, Fishel R.; ''hMSH4-hMSH5 adenosine nucleotide processing and interactions with homologous recombination machinery.''; PubMed Europe PMC
  17. 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
  18. 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
  19. 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
  20. Sehorn MG, Sigurdsson S, Bussen W, Unger VM, Sung P.; ''Human meiotic recombinase Dmc1 promotes ATP-dependent homologous DNA strand exchange.''; PubMed Europe PMC
  21. Thorslund T, Esashi F, West SC.; ''Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1.''; PubMed Europe PMC
  22. Oliver-Bonet M, Campillo M, Turek PJ, Ko E, Martin RH.; ''Analysis of replication protein A (RPA) in human spermatogenesis.''; PubMed Europe PMC
  23. Handel MA, Schimenti JC.; ''Genetics of mammalian meiosis: regulation, dynamics and impact on fertility.''; PubMed Europe PMC
  24. 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
  25. 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
  26. Barlow AL, Hultén MA.; ''Crossing over analysis at pachytene in man.''; PubMed Europe PMC
  27. Baumann P, Benson FE, West SC.; ''Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro.''; PubMed Europe PMC
  28. Benson FE, Baumann P, West SC.; ''Synergistic actions of Rad51 and Rad52 in recombination and DNA repair.''; PubMed Europe PMC
  29. 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
  30. Hayashi K, Yoshida K, Matsui Y.; ''A histone H3 methyltransferase controls epigenetic events required for meiotic prophase.''; PubMed Europe PMC
  31. 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
  32. Inagaki A, Schoenmakers S, Baarends WM.; ''DNA double strand break repair, chromosome synapsis and transcriptional silencing in meiosis.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
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

View all...
NameTypeDatabase referenceComment
3' overhanging DNA

at resected DSB

ends
R-ALL-75156 (Reactome)
3' overhanging DNA at resected DSB ends R-ALL-75156 (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)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDK4ProteinP11802 (Uniprot-TrEMBL)
Cleaved Meiotic Holliday JunctionComplexR-HSA-913201 (Reactome)
DMC1 ProteinQ14565 (Uniprot-TrEMBL)
DMC1ProteinQ14565 (Uniprot-TrEMBL)
DNA R-ALL-29428 (Reactome)
DNA double-strand break ends R-ALL-75165 (Reactome)
DNA double-strand break ends with 3' single-strand breaks R-ALL-9023942 (Reactome)
DNAR-ALL-29428 (Reactome)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFX-NucleosomeComplexR-HSA-975775 (Reactome)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
HOP2(TBPIP):MND1ComplexR-HSA-913509 (Reactome)
Heteroduplex DNA containing D-loop structure R-ALL-83891 (Reactome)
Holliday structure R-ALL-75220 (Reactome)
MLH1 ProteinP40692 (Uniprot-TrEMBL)
MLH1ProteinP40692 (Uniprot-TrEMBL)
MLH3 ProteinQ9UHC1 (Uniprot-TrEMBL)
MLH3ProteinQ9UHC1 (Uniprot-TrEMBL)
MND1 ProteinQ9BWT6 (Uniprot-TrEMBL)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRN:CtIPComplexR-HSA-981776 (Reactome)
MSH4 ProteinO15457 (Uniprot-TrEMBL)
MSH4ProteinO15457 (Uniprot-TrEMBL)
MSH5 ProteinO43196 (Uniprot-TrEMBL)
MSH5ProteinO43196 (Uniprot-TrEMBL)
Me2K5-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me2K5-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Me2K5-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Me3K5-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me3K5-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Me3K5-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Meiotic

single-stranded DNA

complex
ComplexR-HSA-912507 (Reactome)
Meiotic D-loop complexComplexR-HSA-912484 (Reactome)
Meiotic Holliday JunctionComplexR-HSA-912428 (Reactome)
NBN ProteinO60934 (Uniprot-TrEMBL)
Nucleosome with H3K4me2ComplexR-HSA-1214200 (Reactome)
Nucleosome with H3K4me3ComplexR-HSA-1214169 (Reactome)
PRDM9 ProteinQ9NQV7 (Uniprot-TrEMBL)
PRDM9:DNAComplexR-HSA-912415 (Reactome)
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 heterotrimerComplexR-HSA-68462 (Reactome)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
SPO11 DimerComplexR-HSA-912393 (Reactome)
SPO11 ProteinQ9Y5K1 (Uniprot-TrEMBL)
SPO11:double stand breakComplexR-HSA-912365 (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:double strand

break with 3' single strand

breaks
ComplexR-HSA-9023945 (Reactome)
SPO11:oligonucleotideComplexR-HSA-912381 (Reactome)
Single-Stranded Oligodeoxyribonucleotide (12 to 34 nucleotides) R-ALL-912367 (Reactome)
TEX15ProteinQ9BXT5 (Uniprot-TrEMBL)
TOP3A ProteinQ13472 (Uniprot-TrEMBL)
TOP3AProteinQ13472 (Uniprot-TrEMBL)
cleaved Holliday structure R-ALL-83636 (Reactome)
p-S140-H2AFX ProteinP16104 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3' overhanging DNA

at resected DSB

ends
ArrowR-HSA-9023943 (Reactome)
3' overhanging DNA

at resected DSB

ends
R-HSA-912503 (Reactome)
ATMR-HSA-912503 (Reactome)
AdoHcyArrowR-HSA-1214188 (Reactome)
AdoMetR-HSA-1214188 (Reactome)
BLMArrowR-HSA-912429 (Reactome)
BLMR-HSA-912496 (Reactome)
BRCA1R-HSA-912503 (Reactome)
BRCA2ArrowR-HSA-912429 (Reactome)
BRCA2R-HSA-912503 (Reactome)
CDK2R-HSA-912429 (Reactome)
CDK4ArrowR-HSA-912429 (Reactome)
CDK4R-HSA-912503 (Reactome)
Cleaved Meiotic Holliday JunctionArrowR-HSA-912429 (Reactome)
DMC1ArrowR-HSA-912496 (Reactome)
DMC1R-HSA-912503 (Reactome)
DNAR-HSA-912363 (Reactome)
DNAR-HSA-912368 (Reactome)
DNAR-HSA-912458 (Reactome)
H2AFX-NucleosomeR-HSA-912503 (Reactome)
HOP2(TBPIP):MND1ArrowR-HSA-912458 (Reactome)
MLH1R-HSA-912429 (Reactome)
MLH3R-HSA-912429 (Reactome)
MRN:CtIPmim-catalysisR-HSA-9023941 (Reactome)
MRN:CtIPmim-catalysisR-HSA-9023943 (Reactome)
MSH4ArrowR-HSA-912429 (Reactome)
MSH4R-HSA-912496 (Reactome)
MSH5ArrowR-HSA-912429 (Reactome)
MSH5R-HSA-912496 (Reactome)
Meiotic

single-stranded DNA

complex
ArrowR-HSA-912503 (Reactome)
Meiotic

single-stranded DNA

complex
R-HSA-912458 (Reactome)
Meiotic

single-stranded DNA

complex
mim-catalysisR-HSA-912458 (Reactome)
Meiotic D-loop complexArrowR-HSA-912458 (Reactome)
Meiotic D-loop complexR-HSA-912496 (Reactome)
Meiotic Holliday JunctionArrowR-HSA-912496 (Reactome)
Meiotic Holliday JunctionR-HSA-912429 (Reactome)
Nucleosome with H3K4me2R-HSA-1214188 (Reactome)
Nucleosome with H3K4me3ArrowR-HSA-1214188 (Reactome)
PRDM9:DNAArrowR-HSA-912363 (Reactome)
PRDM9:DNAmim-catalysisR-HSA-1214188 (Reactome)
PRDM9R-HSA-912363 (Reactome)
R-HSA-1214188 (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.
R-HSA-9023941 (Reactome) The MRN complex (MRE11:RAD50:NBS1:CtIP) endoncleolytically cleaves a single strand of DNA 3' to SPO11 attached to a double strand break.
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 and exonucleolytic digestion of single strands 3' to the attached SPO11. The overall 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 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.
R-HSA-9023943 (Reactome) The MRN complex (MRE11:RAD50:NBS1:CtIP) exonucleolytically hydrolyzes a single strand of DNA in a 3' to 5' direction starting at a single strand break made by the MRN complex 3' to SPO11.
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 and exonucleolytic digestion of single strands 3' to the attached SPO11. The overall 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 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.
R-HSA-912363 (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.
R-HSA-912368 (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.
R-HSA-912429 (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.
R-HSA-912458 (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).
R-HSA-912496 (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).
R-HSA-912503 (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.
RAD51ArrowR-HSA-912496 (Reactome)
RAD51CArrowR-HSA-912503 (Reactome)
RAD51R-HSA-912503 (Reactome)
RPA heterotrimerArrowR-HSA-912429 (Reactome)
RPA heterotrimerR-HSA-912503 (Reactome)
SPO11 DimerR-HSA-912368 (Reactome)
SPO11 Dimermim-catalysisR-HSA-912368 (Reactome)
SPO11:double stand breakArrowR-HSA-912368 (Reactome)
SPO11:double stand breakR-HSA-9023941 (Reactome)
SPO11:double strand

break with 3' single strand

breaks
ArrowR-HSA-9023941 (Reactome)
SPO11:double strand

break with 3' single strand

breaks
R-HSA-9023943 (Reactome)
SPO11:oligonucleotideArrowR-HSA-9023943 (Reactome)
TEX15ArrowR-HSA-912503 (Reactome)
TOP3AArrowR-HSA-912429 (Reactome)
TOP3AR-HSA-912496 (Reactome)
Personal tools