Transcriptional Regulation by E2F6 (Homo sapiens)

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1-5, 11, 13...11, 1652, 151, 2017, 255158521221, 201515115151815185, 13, 1615151, 14, 198851522, 152cytosolnucleoplasmRING1 PCGF6 BMI1 E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2EED RING1 p-S317,S345-CHEK1E2F6 PRC1L4:UXT geneE2F1 RING1 MGA TFDP2RBBP8 gene E2F6 RYBP E2F1PRC1(BMI1,PCGF2:RYBP:RING1:PHC1,PHC3)E2F6 UXTEPC1MAX RING1 BMI1 PRC1L4:CDC7 geneRNF2 CBX3MGA UXT geneTFDP1 TFDP1 E2F1 gene RNF2 RBBP4 EZH2 CBX3 E2F1 geneAPAF1 gene E2F6 RBBP7 EHMT2 TFDP2 E2F1:TFDP1,TFDP2:RRM2 geneTFDP2 CBX3 RBBP4 gene L3MBTL2 EHMT1 YAF2 RAD51 gene MAX MGA:MAXPCGF6 ATPADPTFDP2 TFDP2 TFDP1 TFDP2 RNF2 RAD51 genePCGF6 RNF2 RNF2 E2F6 E2F6:(TFDP1,TFDP2):CBX5 geneMAX E2F6 RBBP4E2F6:(TFDP1,TFDP2):PRC1 (BMI1,PCGF2:RYBP:RING1:PHC1,PHC3)E2F1:(TFDP1,TFDP2):RAD51 geneE2F6 TFDP2 L3MBTL2 E2F6:(TFDP1.TFDP2):RBBP8 genePHC3 PRC1L4CBX3 CBX5 gene TFDP1 RING1 CDC7E2F1 gene TFDP1 RNF2 E2F6 PCGF2 L3MBTL2 RAD51 gene BRCA1 gene EHMT2 BRCA1 geneRING1 E2F6:TFDP1/2:E2F1geneE2F1 gene APAF1 geneL3MBTL2TFDP1 EHMT1 E2F6:TFDP1:EPC1:PRC2(EZH2) coreEPC1 E2F6:TFDP1EED RRM2MAX E2F6 PCGF6 PHC3 MGA L3MBTL2 PCGF6 EZH2 TFDP2 E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6YAF2 TFDP2 E2F6:TFDP2TFDP1 RNF2 E2F6 TFDP2 CBX3 E2F6:TFDP1:MGA:MAXTFDP2 CBX5RING1 TFDP1 RNF2 E2F6:(TFDP1,TFDP2):RRM2 geneTFDP1 TFDP1 CDC7 geneRING1 MGA RBBP4 geneE2F6 E2F6 E2F6 TFDP1 MGA E2F6:TFDP1:EPC1TFDP2 TFDP2 TFDP2 E2F6:(TFDP1,TFDP2)RING1 PHC1 CDC7 gene p-S12-E2F6YAF2 E2F1 MAX TFDP2 EHMT1:EHMT2CBX3 APAF1 gene PCGF2 EHMT2 TFDP1 RING1 RING1,RNF2TFDP1 PRC1.6(PCGF6:L3MBTL2:RING1,RNF2:YAF2)PCGF6E2F6 E2F6 E2F6:(TFDP1,TFDP2):BRCA1 geneEHMT2 YAF2 TFDP1 E2F6:(TFDP1,TFDP2):RAD51 geneE2F6 UXT gene TFDP1 SUZ12 L3MBTL2 TFDP1 PHC1 TFDP1CBX3 L3MBTL2 E2F6 RBBP7 RRM2 gene TFDP1 RAD51CBX5 geneTFDP1 E2F1 SUZ12 BRCA1E2F6:TFDP1/2,(E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6)TFDP1 PRC2 (EZH2) CoreMGA E2F6:(TFDP1,TFDP2):APAF1 genePCGF6 E2F6 L3MBTL2 E2F6 E2F6 RRM2 genePCGF6 EHMT2 E2F6E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6:E2F1 geneE2F1:(TFDP1,TFDP2)EHMT1 E2F1 E2F6 MAX TFDP1 TFDP1 RBBP8E2F6 TFDP2 RBBP4 TFDP1 EPC1 EHMT1 EHMT1 RBBP8 geneRYBP TFDP2 APAF1E2F1:(TFDP1,TFDP2):APAF1 geneRRM2 gene E2F6:(TFDP1,TFDP2):RBBP4 gene852125182279, 10, 12, 21, 2417551115188201558161515


Description

E2F6, similar to other E2F proteins, possesses the DNA binding domain, the dimerization domain and the marked box. E2F6, however, does not have a pocket protein binding domain and thus does not interact with the retinoblastoma family members RB1, RBL1 (p107) and RBL2 (p130) (Gaubatz et al. 1998, Trimarchi et al. 1998, Cartwright et al. 1998). E2F6 lacks the transactivation domain and acts as a transcriptional repressor (Gaubatz et al. 1998, Trimarchi et al. 1998, Cartwright et al. 1998). E2F6 forms a heterodimer with TFDP1 (DP-1) (Trimarchi et al. 1998, Ogawa et al. 2002, Cartwright et al. 1998) or TFDP2 (DP-2) (Gaubatz et al. 1998, Trimarchi et al. 1998, Cartwright et al. 1998).

E2f6 knockout mice are viable and embryonic fibroblasts derived from these mice proliferate normally. Although E2f6 knockout mice appear healthy, they are affected by homeotic transformations of the axial skeleton, involving vertebrae and ribs. Similar skeletal defects have been reported in mice harboring mutations in polycomb genes, suggesting that E2F6 may function in recruitment of polycomb repressor complex(es) to target promoters (Storre et al. 2002).<p>E2F6 mediates repression of E2F responsive genes. While E2F6 was suggested to maintain G0 state in quiescent cells (Gaubatz et al. 1998, Ogawa et al. 2002), this finding has been challenged (Giangrande et al. 2004, Bertoli et al. 2013, Bertoli et al. 2016). Instead, E2F6-mediated gene repression in proliferating (non-quiescent) cells is thought to repress E2F targets involved in G1/S transition during S phase of the cell cycle. E2F6 does not affect E2F targets involved in G2/M transition (Oberley et al. 2003, Giangrande et al. 2004, Attwooll et al. 2005, Trojer et al. 2011, Bertoli et al. 2013). In the context of the E2F6.com-1 complex, E2F6 was shown to bind to promoters of E2F1, MYC, CDC25A and TK1 genes (Ogawa et al. 2002). E2F6 also binds the promoters of CDC6, RRM1 (RR1), PCNA and TYMS (TS) genes (Giangrande et al. 2004), as well as the promoter of the DHFR gene (Gaubatz et al. 1998). While transcriptional repression by the E2F6.com 1 complex may be associated with histone methyltransferase activity (Ogawa et al. 2002), E2F6 can also repress transcription independently of H3K9 methylation (Oberley et al. 2003).<p>During S phase, E2F6 is involved in the DNA replication stress checkpoint (Bertoli et al. 2013, Bertoli et al. 2016). Under replication stress, CHEK1-mediated phosphorylation prevents association of E2F6 with its target promoters, allowing transcription of E2F target genes whose expression is needed for resolution of stalled replication forks and restart of DNA synthesis. Inability to induce transcription of E2F target genes (due to CHEK1 inhibition or E2F6 overexpression) leads to replication stress induced DNA damage (Bertoli et al. 2013, Bertoli et al. 2016). E2F6 represses transcription of a number of E2F targets involved in DNA synthesis and repair, such as RRM2, RAD51, BRCA1, and RBBP8 (Oberley et al. 2003, Bertoli et al. 2013). View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8953750
Reactome-version 
Reactome version: 62
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

Quality Tags

Ontology Terms

 

Bibliography

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  3. Kuzmichev A, Jenuwein T, Tempst P, Reinberg D.; ''Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3.''; PubMed Europe PMC
  4. Trimarchi JM, Fairchild B, Verona R, Moberg K, Andon N, Lees JA.; ''E2F-6, a member of the E2F family that can behave as a transcriptional repressor.''; PubMed Europe PMC
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  6. Gaubatz S, Wood JG, Livingston DM.; ''Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6.''; PubMed Europe PMC
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  8. Wu M, Wang X, McGregor N, Pienta KJ, Zhang J.; ''Dynamic regulation of Rad51 by E2F1 and p53 in prostate cancer cells upon drug-induced DNA damage under hypoxia.''; PubMed Europe PMC
  9. Cartwright P, Müller H, Wagener C, Holm K, Helin K.; ''E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription.''; PubMed Europe PMC
  10. Bertoli C, Klier S, McGowan C, Wittenberg C, de Bruin RA.; ''Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription.''; PubMed Europe PMC
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  13. Trojer P, Cao AR, Gao Z, Li Y, Zhang J, Xu X, Li G, Losson R, Erdjument-Bromage H, Tempst P, Farnham PJ, Reinberg D.; ''L3MBTL2 protein acts in concert with PcG protein-mediated monoubiquitination of H2A to establish a repressive chromatin structure.''; PubMed Europe PMC
  14. Cao R, Zhang Y.; ''SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.''; PubMed Europe PMC
  15. Giangrande PH, Zhu W, Schlisio S, Sun X, Mori S, Gaubatz S, Nevins JR.; ''A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription.''; PubMed Europe PMC
  16. Hurlin PJ, Steingrìmsson E, Copeland NG, Jenkins NA, Eisenman RN.; ''Mga, a dual-specificity transcription factor that interacts with Max and contains a T-domain DNA-binding motif.''; PubMed Europe PMC
  17. Bertoli C, Herlihy AE, Pennycook BR, Kriston-Vizi J, de Bruin RAM.; ''Sustained E2F-Dependent Transcription Is a Key Mechanism to Prevent Replication-Stress-Induced DNA Damage.''; PubMed Europe PMC
  18. Yang WW, Shu B, Zhu Y, Yang HT.; ''E2F6 inhibits cobalt chloride-mimetic hypoxia-induced apoptosis through E2F1.''; PubMed Europe PMC
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History

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CompareRevisionActionTimeUserComment
101421view11:30, 1 November 2018ReactomeTeamreactome version 66
100959view21:07, 31 October 2018ReactomeTeamreactome version 65
100496view19:41, 31 October 2018ReactomeTeamreactome version 64
100041view16:24, 31 October 2018ReactomeTeamreactome version 63
99594view14:58, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99374view13:19, 31 October 2018DeSlOntology Term : 'regulatory pathway' added !
99371view12:48, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
APAF1 gene ProteinENSG00000120868 (Ensembl)
APAF1 geneGeneProductENSG00000120868 (Ensembl)
APAF1ProteinO14727 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BMI1 ProteinP35226 (Uniprot-TrEMBL)
BRCA1 gene ProteinENSG00000012048 (Ensembl)
BRCA1 geneGeneProductENSG00000012048 (Ensembl)
BRCA1ProteinP38398 (Uniprot-TrEMBL)
CBX3 ProteinQ13185 (Uniprot-TrEMBL)
CBX3ProteinQ13185 (Uniprot-TrEMBL)
CBX5 gene ProteinENSG00000094916 (Ensembl)
CBX5 geneGeneProductENSG00000094916 (Ensembl)
CBX5ProteinP45973 (Uniprot-TrEMBL)
CDC7 gene ProteinENSG00000097046 (Ensembl)
CDC7 geneGeneProductENSG00000097046 (Ensembl)
CDC7ProteinO00311 (Uniprot-TrEMBL)
E2F1 ProteinQ01094 (Uniprot-TrEMBL)
E2F1 gene ProteinENSG00000101412 (Ensembl)
E2F1 geneGeneProductENSG00000101412 (Ensembl)
E2F1:(TFDP1,TFDP2):APAF1 geneComplexR-HSA-9007509 (Reactome)
E2F1:(TFDP1,TFDP2):RAD51 geneComplexR-HSA-9007572 (Reactome)
E2F1:(TFDP1,TFDP2)ComplexR-HSA-9007512 (Reactome)
E2F1:TFDP1,TFDP2:RRM2 geneComplexR-HSA-8961974 (Reactome)
E2F1ProteinQ01094 (Uniprot-TrEMBL)
E2F6 ProteinO75461 (Uniprot-TrEMBL)
E2F6:(TFDP1,TFDP2):APAF1 geneComplexR-HSA-9007527 (Reactome)
E2F6:(TFDP1,TFDP2):BRCA1 geneComplexR-HSA-9007604 (Reactome)
E2F6:(TFDP1,TFDP2):CBX5 geneComplexR-HSA-9007645 (Reactome)
E2F6:(TFDP1,TFDP2):PRC1 (BMI1,PCGF2:RYBP:RING1:PHC1,PHC3)ComplexR-HSA-8954081 (Reactome)
E2F6:(TFDP1,TFDP2):RAD51 geneComplexR-HSA-9007547 (Reactome)
E2F6:(TFDP1,TFDP2):RBBP4 geneComplexR-HSA-9007633 (Reactome)
E2F6:(TFDP1,TFDP2):RRM2 geneComplexR-HSA-9007590 (Reactome)
E2F6:(TFDP1,TFDP2)ComplexR-HSA-9007225 (Reactome)
E2F6:(TFDP1.TFDP2):RBBP8 geneComplexR-HSA-9007616 (Reactome)
E2F6:TFDP1/2,(E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6)ComplexR-HSA-8953577 (Reactome)
E2F6:TFDP1/2:E2F1 geneComplexR-HSA-9007222 (Reactome)
E2F6:TFDP1:EPC1:PRC2 (EZH2) coreComplexR-HSA-8954116 (Reactome)
E2F6:TFDP1:EPC1ComplexR-HSA-8954113 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6:E2F1 geneComplexR-HSA-8953550 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6ComplexR-HSA-8953987 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2ComplexR-HSA-8953419 (Reactome)
E2F6:TFDP1:MGA:MAXComplexR-HSA-8953118 (Reactome)
E2F6:TFDP1ComplexR-HSA-8953103 (Reactome)
E2F6:TFDP2ComplexR-HSA-8954055 (Reactome)
E2F6ProteinO75461 (Uniprot-TrEMBL)
EED ProteinO75530 (Uniprot-TrEMBL)
EHMT1 ProteinQ9H9B1 (Uniprot-TrEMBL)
EHMT1:EHMT2ComplexR-HSA-3788728 (Reactome)
EHMT2 ProteinQ96KQ7 (Uniprot-TrEMBL)
EPC1 ProteinQ9H2F5 (Uniprot-TrEMBL)
EPC1ProteinQ9H2F5 (Uniprot-TrEMBL)
EZH2 ProteinQ15910 (Uniprot-TrEMBL)
L3MBTL2 ProteinQ969R5 (Uniprot-TrEMBL)
L3MBTL2ProteinQ969R5 (Uniprot-TrEMBL)
MAX ProteinP61244 (Uniprot-TrEMBL)
MGA ProteinQ8IWI9 (Uniprot-TrEMBL)
MGA:MAXComplexR-HSA-8953100 (Reactome)
PCGF2 ProteinP35227 (Uniprot-TrEMBL)
PCGF6 ProteinQ9BYE7 (Uniprot-TrEMBL)
PCGF6ProteinQ9BYE7 (Uniprot-TrEMBL)
PHC1 ProteinP78364 (Uniprot-TrEMBL)
PHC3 ProteinQ8NDX5 (Uniprot-TrEMBL)
PRC1 (BMI1,PCGF2:RYBP:RING1:PHC1,PHC3)ComplexR-HSA-9007669 (Reactome)
PRC1.6 (PCGF6:L3MBTL2:RING1,RNF2:YAF2)ComplexR-HSA-9007266 (Reactome)
PRC1L4:CDC7 geneComplexR-HSA-9007466 (Reactome)
PRC1L4:UXT geneComplexR-HSA-9007476 (Reactome)
PRC1L4ComplexR-HSA-9007446 (Reactome)
PRC2 (EZH2) CoreComplexR-HSA-212285 (Reactome) The human Polycomb Repressive Complex 2 (PRC2) is homologous to the Drosophila PRC2. The core PRC2 contains EZH2, a histone methyltransferase specific for lysine 27 and lysine 9 of histone H3. The methyltransferase activity of EZH2 is dependent on its association with PRC2. The complex contains other uncharacterized proteins, its composition may vary in different tissues and developmental stages, and the order of assembly of the complex is presently unknown.
RAD51 gene ProteinENSG00000051180 (Ensembl)
RAD51 geneGeneProductENSG00000051180 (Ensembl)
RAD51ProteinQ06609 (Uniprot-TrEMBL)
RBBP4 ProteinQ09028 (Uniprot-TrEMBL)
RBBP4 gene ProteinENSG00000162521 (Ensembl)
RBBP4 geneGeneProductENSG00000162521 (Ensembl)
RBBP4ProteinQ09028 (Uniprot-TrEMBL)
RBBP7 ProteinQ16576 (Uniprot-TrEMBL)
RBBP8 gene ProteinENSG00000101773 (Ensembl)
RBBP8 geneGeneProductENSG00000101773 (Ensembl)
RBBP8ProteinQ99708 (Uniprot-TrEMBL)
RING1 ProteinQ06587 (Uniprot-TrEMBL)
RING1,RNF2ComplexR-HSA-9007201 (Reactome)
RNF2 ProteinQ99496 (Uniprot-TrEMBL)
RRM2 gene ProteinENSG00000171848 (Ensembl)
RRM2 geneGeneProductENSG00000171848 (Ensembl)
RRM2ProteinP31350 (Uniprot-TrEMBL)
RYBP ProteinQ8N488 (Uniprot-TrEMBL)
SUZ12 ProteinQ15022 (Uniprot-TrEMBL)
TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP1ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TFDP2ProteinQ14188 (Uniprot-TrEMBL)
UXT gene ProteinENSG00000126756 (Ensembl)
UXT geneGeneProductENSG00000126756 (Ensembl)
UXTProteinQ9UBK9 (Uniprot-TrEMBL)
YAF2 ProteinQ8IY57 (Uniprot-TrEMBL)
p-S12-E2F6ProteinO75461 (Uniprot-TrEMBL)
p-S317,S345-CHEK1ProteinO14757 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9007539 (Reactome)
APAF1 geneR-HSA-9007496 (Reactome)
APAF1 geneR-HSA-9007514 (Reactome)
APAF1 geneR-HSA-9007522 (Reactome)
APAF1ArrowR-HSA-9007496 (Reactome)
ATPR-HSA-9007539 (Reactome)
BRCA1 geneR-HSA-9007605 (Reactome)
BRCA1 geneR-HSA-9007606 (Reactome)
BRCA1ArrowR-HSA-9007605 (Reactome)
CBX3R-HSA-9007283 (Reactome)
CBX3R-HSA-9007447 (Reactome)
CBX5 geneR-HSA-9007646 (Reactome)
CBX5 geneR-HSA-9007647 (Reactome)
CBX5ArrowR-HSA-9007646 (Reactome)
CDC7 geneR-HSA-9007462 (Reactome)
CDC7 geneR-HSA-9007467 (Reactome)
CDC7ArrowR-HSA-9007462 (Reactome)
E2F1 geneR-HSA-8953452 (Reactome)
E2F1 geneR-HSA-8953556 (Reactome)
E2F1 geneR-HSA-9007220 (Reactome)
E2F1:(TFDP1,TFDP2):APAF1 geneArrowR-HSA-9007496 (Reactome)
E2F1:(TFDP1,TFDP2):APAF1 geneArrowR-HSA-9007514 (Reactome)
E2F1:(TFDP1,TFDP2):RAD51 geneArrowR-HSA-9007561 (Reactome)
E2F1:(TFDP1,TFDP2):RAD51 geneArrowR-HSA-9007582 (Reactome)
E2F1:(TFDP1,TFDP2)R-HSA-9007514 (Reactome)
E2F1:(TFDP1,TFDP2)R-HSA-9007561 (Reactome)
E2F1:TFDP1,TFDP2:RRM2 geneArrowR-HSA-8961982 (Reactome)
E2F1ArrowR-HSA-8953556 (Reactome)
E2F6:(TFDP1,TFDP2):APAF1 geneArrowR-HSA-9007522 (Reactome)
E2F6:(TFDP1,TFDP2):APAF1 geneTBarR-HSA-9007496 (Reactome)
E2F6:(TFDP1,TFDP2):BRCA1 geneArrowR-HSA-9007606 (Reactome)
E2F6:(TFDP1,TFDP2):BRCA1 geneTBarR-HSA-9007605 (Reactome)
E2F6:(TFDP1,TFDP2):CBX5 geneArrowR-HSA-9007647 (Reactome)
E2F6:(TFDP1,TFDP2):CBX5 geneTBarR-HSA-9007646 (Reactome)
E2F6:(TFDP1,TFDP2):PRC1 (BMI1,PCGF2:RYBP:RING1:PHC1,PHC3)ArrowR-HSA-8954082 (Reactome)
E2F6:(TFDP1,TFDP2):RAD51 geneArrowR-HSA-9007546 (Reactome)
E2F6:(TFDP1,TFDP2):RAD51 geneTBarR-HSA-9007582 (Reactome)
E2F6:(TFDP1,TFDP2):RBBP4 geneArrowR-HSA-9007631 (Reactome)
E2F6:(TFDP1,TFDP2):RBBP4 geneTBarR-HSA-9007640 (Reactome)
E2F6:(TFDP1,TFDP2):RRM2 geneArrowR-HSA-9007591 (Reactome)
E2F6:(TFDP1,TFDP2):RRM2 geneTBarR-HSA-8961982 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-8954082 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007220 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007522 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007546 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007591 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007606 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007615 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007631 (Reactome)
E2F6:(TFDP1,TFDP2)R-HSA-9007647 (Reactome)
E2F6:(TFDP1.TFDP2):RBBP8 geneArrowR-HSA-9007615 (Reactome)
E2F6:(TFDP1.TFDP2):RBBP8 geneTBarR-HSA-9007625 (Reactome)
E2F6:TFDP1/2,(E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6)TBarR-HSA-8953556 (Reactome)
E2F6:TFDP1/2:E2F1 geneArrowR-HSA-9007220 (Reactome)
E2F6:TFDP1:EPC1:PRC2 (EZH2) coreArrowR-HSA-8954110 (Reactome)
E2F6:TFDP1:EPC1ArrowR-HSA-8954117 (Reactome)
E2F6:TFDP1:EPC1R-HSA-8954110 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6:E2F1 geneArrowR-HSA-8953452 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6ArrowR-HSA-9007283 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2:CBX3:PRC1.6R-HSA-8953452 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2ArrowR-HSA-8953418 (Reactome)
E2F6:TFDP1:MGA:MAX:EHMT1:EHMT2R-HSA-9007283 (Reactome)
E2F6:TFDP1:MGA:MAXArrowR-HSA-8953115 (Reactome)
E2F6:TFDP1:MGA:MAXR-HSA-8953418 (Reactome)
E2F6:TFDP1ArrowR-HSA-8953111 (Reactome)
E2F6:TFDP1R-HSA-8953115 (Reactome)
E2F6:TFDP1R-HSA-8954117 (Reactome)
E2F6:TFDP2ArrowR-HSA-8954056 (Reactome)
E2F6R-HSA-8953111 (Reactome)
E2F6R-HSA-8954056 (Reactome)
E2F6R-HSA-9007447 (Reactome)
E2F6R-HSA-9007539 (Reactome)
EHMT1:EHMT2R-HSA-8953418 (Reactome)
EPC1R-HSA-8954117 (Reactome)
L3MBTL2R-HSA-9007447 (Reactome)
MGA:MAXR-HSA-8953115 (Reactome)
PCGF6R-HSA-9007447 (Reactome)
PRC1 (BMI1,PCGF2:RYBP:RING1:PHC1,PHC3)R-HSA-8954082 (Reactome)
PRC1.6 (PCGF6:L3MBTL2:RING1,RNF2:YAF2)R-HSA-9007283 (Reactome)
PRC1L4:CDC7 geneArrowR-HSA-9007467 (Reactome)
PRC1L4:CDC7 geneTBarR-HSA-9007462 (Reactome)
PRC1L4:UXT geneArrowR-HSA-9007464 (Reactome)
PRC1L4:UXT geneTBarR-HSA-9007465 (Reactome)
PRC1L4ArrowR-HSA-9007447 (Reactome)
PRC1L4R-HSA-9007464 (Reactome)
PRC1L4R-HSA-9007467 (Reactome)
PRC2 (EZH2) CoreR-HSA-8954110 (Reactome)
R-HSA-8953111 (Reactome) E2F6, an E2F family member without the pocket protein-binding domain and transactivation domain (Gaubatz et al. 1998), forms a heterodimer with TFDP1 (DP-1) (Cartwright et al. 1998, Trimarchi et al. 1998, Ogawa et al. 2002).
R-HSA-8953115 (Reactome) The E2F6 heterodimer with TFDP1 forms a complex with the heterodimer of MGA and MAX transcription factors. The E2F6:TFDP1:MGA:MAX complex is the core of the E2F6.com-1 complex and is able to bind to E2F, Myc and Brachyury (T box) binding elements in DNA (Ogawa et al. 2002).
R-HSA-8953418 (Reactome) The complex of histone methyltransferases EHMT1 (GLP) and EHMT2 (G9a) is recruited to the core E2F6.com-1 complex, consisting of E2F6, TFDP1 (DP-1), MGA and MAX (Ogawa et al. 2002).
R-HSA-8953452 (Reactome) The E2F6.com-1 complex, consisting of transcription factors E2F6, TFDP1 (DP 1), MGA, MAX, histone methyltransferases EHMT1 (GLP) and EHMT2 (G9a), in complex with CBX3 (HP1gamma) and likely PRC1.6, binds to the E2F1 gene promoter. Presence of PRC1.6 components at the E2F1 gene promoter has not been tested, but is assumed based on association of PRC1.6-interacting protein CBX3 with the E2F1 promoter and the joint binding of CBX3 and PRC1.6 to the E2F6.com-1 complex (Ogawa et al. 2002). Besides the E2F1 gene promoter, the complex of E2F6.com-1 with CBX3 and possibly PRC1.6 was shown to bind to promoters of other genes involved in cell cycle progression, namely MYC, CDC25A and TK1 (Ogawa et al. 2002). However, transcriptional regulation of MYC, CDC25A and TK1 by E2F6 has not been directly demonstrated, and therefore association of E2F6 with these gene loci is not shown.
R-HSA-8953556 (Reactome) The E2F1 gene transcription is inhibited by binding of E2F6 to the E2F1 gene promoter (Yang et al. 2008). E2F6 is assumed to be in the complex with at least TFDP1 or TFDP2. The E2F6.com-1 complex, consisting of E2F6, TFDP1 (DP-1), MGA, MAX, EHMT1 (GLP) and EHMT2 (G9a), associated with CBX3 (HP1gamma) and probably the PRC1.6 complex, also binds to the E2F1 gene promoter. While repression of E2F1 transcription by the E2F6.com-1 complex has not been examined, this complex is thought to introduce repressive H3K9Me epigenetic marks on chromatin. Therefore, E2F6.com-1 complex is shown as a candidate repressor of the E2F1 gene transcription (Ogawa et al. 2002). E2F6-mediated repression of E2F1 is implicated in inhibition of cell cycle entry and maintenance of G0 state (cellular quiescence) (Ogawa et al. 2002), which has been challenged by more recent studies (Giangrande et al. 2004, Bertoli et al. 2013, Bertoli et al. 2016), but also in the inhibition of E2F1-mediated apoptosis (Yang et al. 2008).
R-HSA-8954056 (Reactome) E2F6 forms a heterodimer with TFDP2 (DP-2) (Gaubatz et al. 1998, Trimarchi et al. 1998). The E2F6:TFDP2 complex binds to the E2F binding site in the promoter of the DHFR gene, encoding Dihydrofolate reductase, in vitro (Gaubatz et al. 1998). E2F6 presumably represses DHFR transcription, but this has not been experimentally confirmed. It is not known whether other E2F6 and/or TFDP2 binding proteins are recruited to the DHFR promoter.
R-HSA-8954082 (Reactome) E2F6, presumably in complex with TFDP1 (DP-1) or TFDP2 (DP-2), interacts with components of the Polycomb group (PcG) complex PRC1: BMI1, RYBP, RING1 (RING1A), PCGF2 (MEL-18) and PHC1 (mPH1) (Trimarchi et al. 2001), as well as PHC3 (Deshpande et al. 2007). The PRC1 complex may contribute to E2F6-mediated transcriptional repression. PHC3 exhibits frequent loss of heterozygosity (LoH) in primary human osteosarcoma tumors (Deshpande et al. 2007).
R-HSA-8954110 (Reactome) In late G1 and in S phase of the cell cycle, the complex of E2F6, TFDP1 and EPC1 interacts with EZH2, a component of the Polycomb group complex PRC2. EZH2 directly binds to E2F6. EED, another component of the PRC2 complex, co-immunoprecipitates with EZH2 and co-elutes with the E2F6-containing cell fraction. Co-immunoprecipitation of other components of the PRC2 complex with E2F6 has not been examined. It is suggested that the complex of E2F6 and PRC2 regulates expression of genes needed for cell cycle progression (Attwooll et al. 2005).
R-HSA-8954117 (Reactome) The heterodimer of E2F6 and TFDP1 (DP-1) forms a stable tripartite complex with EPC1. EPC1 is a component of the NuA4 histone acetyltransferase complex. The complex of E2F6 and EPC1 acts as a repressive complex in a CAT reporter assay, but the presence of other NuA4 components has not been detected in co-immunoprecipitates of E2F6 and EPC1. EPC1 directly interacts with E2F6 but not with TFDP1 (Attwooll et al. 2005).
R-HSA-8961982 (Reactome) E2F1 directly stimulates transcription of the RRM2 gene, encoding Ribonucleoside-diphosphate reductase subunit M2 (DeGregori et al. 1995, Giangrande et al. 2004). Binding of E2F6 to the RRM2 gene promoter inhibits RRM2 transcription (Bertoli et al. 2013).
R-HSA-9007220 (Reactome) E2F6 binds to the promoter of the E2F1 gene. It has not been tested whether E2F6 binds to the E2F1 promoter in the context of the E2F6:TFDP1 or E2F6:TFDP2 complex, or both (Yang et al. 2008).
R-HSA-9007283 (Reactome) CBX3 (HP1gamma) and the polycomb group (PcG) repressor complex PRC1.6 associate with the E2F6.com-1 complex. The PRC1.6 complex shown to associate with E2F6 consists of PCGF6 (MBLR), RING1 (RING1A) or RNF2 (RING2, also known as RING1B), YAF2 and L3MBTL2. The E2F6.com-1 complex is composed of E2F6, TFDP1 (DP-1), MGA, MAX, EHMT1 (GLP) and EHMT2 (G9a). This complex likely has a histone H3 methyltransferase activity and may be involved in creating the repressive H3K9Me mark at target genes, which would result in transcriptional repression (Ogawa et al. 2002).
R-HSA-9007447 (Reactome) E2F6 forms a complex with CBX3 (HP1gamma) and components of the polycomb repressor complex PRC1.6: PCGF6 (MBLR), L3MBTL2, RING1 (RING1A) or RNF2 (RING2, also known as RING2B). This polycomb repressor-like complex is named PRC1L4. Unlike the complex composed of E2F6.com-1, PRC1.6 and CBX3 (Ogawa et al. 2002), the PRC1L4 complex does not possess histone methyltransferase activity. Instead, the PRC1L4 complex may have a histone E3-ubiquitin ligase activity. The PRC1L4 complex was shown to bind to promoters of several genes: CDC7, CSTF3, MCM3, UXT, RPA2, RAD51C, RFC3, HOXC5. Of these genes, transcriptional repression was tested and demonstrated for CDC7 and UXT (Trojer et al. 2011).
R-HSA-9007462 (Reactome) Binding of the PRC1L4 complex, composed of E2F6, CBX3 (HP1gamma), PCGF6 (MBLR), L3MBTL2 and RING1 or RNF2, to the CDC7 gene promoter represses CDC7 transcription. This is concluded based on experimental evidence of direct association of the PRC1L4 complex with the CDC7 gene promoter and increased CDC7 expression upon E2F6 or L3MBTL2 knockdown (Trojer et al. 2011).
R-HSA-9007464 (Reactome) The PRC1L4 complex, consisting of E2F6, CBX3 (HP1gamma), PCGF6 (MBLR), L3MBTL2, and RING1 (RING1A) or RNF2 (RING2, also known as RING1B), binds the promoter of the UXT gene (Trojer et al. 2011). E2F6 was also reported to bind to the UXT promoter by Oberley et al. 2003.
R-HSA-9007465 (Reactome) Binding of the PRC1L4 complex, composed of E2F6, CBX3 (HP1gamma), PCGF6 (MBLR), L3MBTL2 and RING1 or RNF2, to the UXT gene promoter represses UXT transcription. This is concluded based on experimental evidence of direct association of the PRC1L4 complex with the UXT gene promoter and increased UXT expression upon E2F6 or L3MBTL2 knockdown (Trojer et al. 2011). E2F6 was also reported as a repressor of the UXT gene transcription by Oberley et al. 2013.
R-HSA-9007467 (Reactome) The PRC1L4 complex, consisting of E2F6, CBX3 (HP1gamma), PCGF6 (MBLR), L3MBTL2, and RING1 (RING1A) or RNF2 (RING2, also known as RING1B), binds the promoter of the CDC7 gene (Trojer et al. 2011).
R-HSA-9007496 (Reactome) Expression of the pro-apoptotic APAF1 gene is directly stimulated by E2F1 binding to the APAF1 promoter. E2F6 can compete with E2F1 for the E2F binding site in the APAF1 promoter. Binding of E2F6 to the APAF1 promoter represses APAF1 transcription, which is implicated in suppression of growth-associated apoptosis in human hematopoietic progenitor cells (Kikuchi et al. 2007).
R-HSA-9007514 (Reactome) E2F1, presumably in complex with TFDP1 or TFDP2, binds the promoter of the APAF1 gene (Kikuchi et al. 2007).
R-HSA-9007522 (Reactome) E2F6, presumably in complex with TFDP1 (DP-1) or TFDP2 (DP-2), binds to the promoter of the APAF1 gene (Kikuchi et al. 2007).
R-HSA-9007539 (Reactome) CHEK1 (Chk1), activated by ATR in response to replication stress (stalled replication forks), phosphorylates E2F6 on serine residue S12 and possibly also on serine residue S52. CHEK1-mediated phosphorylation prevents association of E2F6 with its target promoters, allowing transcription of E2F target genes whose expression is needed for resolution of stalled replication forks and restart of DNA synthesis. Inability to induce transcription of E2F target genes (due to CHEK1 inhibition or E2F6 overexpression) leads to replication stress-induced DNA damage (Bertoli et al. 2013, Bertoli et al. 2016). It has not been clarified whether CHEK1 phosphorylates E2F6 in the context of the E2F6 complex with TFDP1/TFDP2.
R-HSA-9007546 (Reactome) E2F6, presumably in complex with at least TFDP1 (DP-1) or TFDP2 (DP-2), binds the promoter of the RAD51 gene. Binding of E2F6 to the RAD51 promoter is inhibited by CHEK1-mediated phosphorylation of E2F6 (Bertoli et al. 2013).
R-HSA-9007561 (Reactome) E2F1, presumably in complex with TFDP1 (DP-1) or TFDP2 (DP-2) binds the promoter of the RAD51 gene (Bertoli et al. 2013, Wu et al. 2014).
R-HSA-9007582 (Reactome) Transcription of the RAD51 gene is directly stimulated by E2F1 (Wu et al. 2014) and inhibited by E2F6 (Bertoli et al. 2013).
R-HSA-9007591 (Reactome) E2F6, presumably in complex with at least TFDP1 (DP-1) or TFDP2 (DP-2), binds the promoter of the E2F1 target gene RRM2. Binding of E2F6 to the RRM2 promoter is inhibited by CHEK1 mediated phosphorylation of E2F6 (Bertoli et al. 2013).
R-HSA-9007605 (Reactome) BRCA1 gene transcription is inhibited by binding of E2F6 to the promoter of the BRCA1 gene (Oberley et al. 2003).
R-HSA-9007606 (Reactome) E2F6, presumably in complex with at least TFDP1 (DP-1) or TFDP2 (DP-2), binds the promoter of the BRCA1 gene (Oberley et al. 2013).
R-HSA-9007615 (Reactome) E2F6, presumably in complex with at least TFDP1 (DP-1) or TFDP2 (DP-2), binds the promoter of the RBBP8 (CtIP) gene (Oberley et al. 2003).
R-HSA-9007625 (Reactome) Expression of the RBBP8 (CtIP) gene is inhibited by binding of E2F6 to the RBBP8 promoter (Oberley et al. 2003).
R-HSA-9007631 (Reactome) E2F6, presumably in complex with at least TFDP1 (DP-1) or TFDP2 (DP-2), binds the promoter of the RBBP4 (RbAp48) gene (Oberley et al. 2003).
R-HSA-9007640 (Reactome) Transcription of the RBBP4 (RbAp48) gene is inhibited by binding of E2F6 to the RBBP4 promoter (Oberley et al. 2003).
R-HSA-9007646 (Reactome) Transcription of the CBX5 (HP1alpha) gene is inhibited by binding of E2F6 to the CBX5 promoter (Oberley et al. 2003).
R-HSA-9007647 (Reactome) E2F6, presumably in complex with at least TFDP1 (DP-1) or TFDP2 (DP-2), binds the promoter of the CBX5 (HP1alpha) gene (Oberley et al. 2003).
RAD51 geneR-HSA-9007546 (Reactome)
RAD51 geneR-HSA-9007561 (Reactome)
RAD51 geneR-HSA-9007582 (Reactome)
RAD51ArrowR-HSA-9007582 (Reactome)
RBBP4 geneR-HSA-9007631 (Reactome)
RBBP4 geneR-HSA-9007640 (Reactome)
RBBP4ArrowR-HSA-9007640 (Reactome)
RBBP8 geneR-HSA-9007615 (Reactome)
RBBP8 geneR-HSA-9007625 (Reactome)
RBBP8ArrowR-HSA-9007625 (Reactome)
RING1,RNF2R-HSA-9007447 (Reactome)
RRM2 geneR-HSA-8961982 (Reactome)
RRM2 geneR-HSA-9007591 (Reactome)
RRM2ArrowR-HSA-8961982 (Reactome)
TFDP1R-HSA-8953111 (Reactome)
TFDP2R-HSA-8954056 (Reactome)
UXT geneR-HSA-9007464 (Reactome)
UXT geneR-HSA-9007465 (Reactome)
UXTArrowR-HSA-9007465 (Reactome)
p-S12-E2F6ArrowR-HSA-9007539 (Reactome)
p-S317,S345-CHEK1TBarR-HSA-9007546 (Reactome)
p-S317,S345-CHEK1TBarR-HSA-9007591 (Reactome)
p-S317,S345-CHEK1mim-catalysisR-HSA-9007539 (Reactome)

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