E2F6 转录调控
中文名称
通路描述
E2F6 与其他 E2F 蛋白类似，具有 DNA 结合域、二聚化域和标记盒，但不具有 pocket 蛋白结合域，因此不与视网膜母细胞瘤家族成员 RB1、RBL1 (p107) 和 RBL2 (p130) 相互作用 (Gaubatz et al. 1998, Trimarchi et al. 1998, Cartwright et al. 1998)。E2F6 缺乏转录激活域，作为转录抑制因子发挥作用 (Gaubatz et al. 1998, Trimarchi et al. 1998, Cartwright et al. 1998)。E2F6 与 TFDP1 (DP-1) 形成异二聚体 (Trimarchi et al. 1998, Ogawa et al. 2002, Cartwright et al. 1998) 或与 TFDP2 (DP-2) 形成异二聚体 (Gaubatz et al. 1998, Trimarchi et al. 1998, Cartwright et al. 1998)。E2f6 敲除小鼠存活且胚胎成纤维细胞增殖正常。尽管 E2f6 敲除小鼠外观健康，但它们受轴向骨骼的同型转变影响，涉及椎骨和肋骨。类似骨骼缺陷已在携带 polycomb 基因突变的小鼠中报道，表明 E2F6 可能在招募 polycomb 抑制复合物到靶启动子中发挥作用 (Storre et al. 2002)。E2F6 介导对 E2F 响应基因的抑制。虽然 E2F6 被建议维持静止细胞中的 G0 状态 (Gaubatz et al. 1998, Ogawa et al. 2002)，但该发现受到挑战 (Giangrande et al. 2004, Bertoli et al. 2013, Bertoli et al. 2016)。相反，E2F6 介导的增殖细胞 (非静止) 中的基因抑制被认为抑制细胞周期 S 期 G1/S 转换中涉及 E2F 靶基因的转录。E2F6 不影响 E2F 靶基因涉及 G2/M 转换 (Oberley et al. 2003, Giangrande et al. 2004, Attwooll et al. 2005, Trojer et al. 2011, Bertoli et al. 2013)。在 E2F6.com-1 复合物中，E2F6 被证明与 E2F1、MYC、CDC25A 和 TK1 基因的启动子结合 (Ogawa et al. 2002)。E2F6 还与 CDC6、RRM1 (RR1)、PCNA 和 TYMS (TS) 基因的启动子结合 (Giangrande et al. 2004)，以及 DHFR 基因的启动子结合 (Gaubatz et al. 1998)。虽然 E2F6.com-1 复合物的转录抑制可能与组蛋白甲基转移酶活性相关 (Ogawa et al. 2002)，但 E2F6 也可在不依赖 H3K9 甲基化的情况下抑制转录 (Oberley et al. 2003)。在 S 期，E2F6 参与 DNA 复制应激检查点 (Bertoli et al. 2013, Bertoli et al. 2016)。在复制应激下，CHEK1 介导的磷酸化阻止 E2F6 与其靶启动子的结合，允许转录那些需要解决停滞复制叉并重启 DNA 合成的 E2F 靶基因的表达。由于 CHEK1 抑制或 E2F6 过表达导致 E2F 靶基因转录不能诱导，引发复制应激诱导的 DNA 损伤 (Bertoli et al. 2013, Bertoli et al. 2016)。E2F6 抑制 DNA 合成和修复中涉及多个 E2F 靶基因的转录，如 RRM2、RAD51、BRCA1 和 RBBP8 (Oberley et al. 2003, Bertoli et al. 2013)。
英文描述
Transcriptional Regulation by E2F6 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 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).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).
所含基因
34 个基因