Transcriptional Regulation by E2F6

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Homo sapiens
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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).

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 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 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).

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).

Literature References
PubMed ID Title Journal Year
9704927 E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription

Cartwright, P, Müller, H, Wagener, C, Holm, K, Helin, K

Oncogene 1998
9501179 E2F-6, a member of the E2F family that can behave as a transcriptional repressor

Trimarchi, JM, Fairchild, B, Verona, R, Moberg, K, Andon, N, Lees, JA

Proc. Natl. Acad. Sci. U.S.A. 1998
12004135 A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells

Ogawa, H, Ishiguro, K, Gaubatz, S, Livingston, DM, Nakatani, Y

Science 2002
15574595 A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription

Giangrande, PH, Zhu, W, Schlisio, S, Sun, X, Mori, S, Gaubatz, S, Nevins, JR

Genes Dev. 2004
12101104 Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6

Storre, J, Elsässer, HP, Fuchs, M, Ullmann, D, Livingston, DM, Gaubatz, S

EMBO Rep. 2002
23954429 Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription

Bertoli, C, Klier, S, McGowan, C, Wittenberg, C, de Bruin, RA

Curr. Biol. 2013
21596310 L3MBTL2 protein acts in concert with PcG protein-mediated monoubiquitination of H2A to establish a repressive chromatin structure

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

Mol. Cell 2011
9689056 Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6

Gaubatz, S, Wood, JG, Livingston, DM

Proc. Natl. Acad. Sci. U.S.A. 1998
12909625 E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9

Oberley, MJ, Inman, DR, Farnham, PJ

J. Biol. Chem. 2003
27160911 Sustained E2F-Dependent Transcription Is a Key Mechanism to Prevent Replication-Stress-Induced DNA Damage

Bertoli, C, Herlihy, AE, Pennycook, BR, Kriston-Vizi, J, de Bruin, RA

Cell Rep 2016
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