复制原点组装
中文名称
通路描述
人类 ORC1 可独立于其他复制原点复合物（ORC）亚基与复制原点位点结合。ORC1 在早期有丝分裂（M 期）定位于凝缩染色体中，作为 ORC 及随后复制前复合物组装的核启动中心。ORC1 在整个 S 期晚期复制原点持续结合。进入 S 期时，ORC1 发生泛素介导的降解，导致 ORC 从染色质上解离。
大多数人类复制原点包含富含鸟嘌呤（G）的序列，可能形成 G-四链体（G4）结构（Besnard et al. 2012），这些 G4 结构可能介导 ORC1 对复制原点的识别（Hoshina et al. 2013; Eladl et al. 2021）。除了结合无核小体复制原点 DNA 外，ORC1 还与相邻的核小体相互作用（Hizume et al. 2013），特别是富含 H4 二聚体在赖氨酸 21 甲基化（H4K20me2 标记）的核小体，该标记在复制原点中富集。ORC1 结合 H4K20me2 促进 ORC1 结合复制原点及 ORC 染色质加载（Kuo et al. 2012, Zhang et al. 2015）。
ORC1 结合位点普遍与编码和非编码 RNA 的转录起始位点（TSS）相关联。与中等至高转录水平的 TSS 相关的复制原点（属于编码 RNA）在早期 S 期启动，而与低转录水平的 TSS 相关的复制原点（属于非编码 RNA）在整个 S 期启动（Dellino et al. 2013）。
ORC2 与 ORC3 形成异二聚体，这是 ORC5 及随后 ORC4 结合的前提条件（Ranjan and Gossen 2006; Siddiqui and Stillman 2007）。ORC1 与核内的 ORC(2-5) 复合物结合形成稳定的 ORC(1-5) 复合物（Radichev et al. 2006; Ghosh et al. 2011）。ORC1 对于 ORC(2-5) 复合物结合染色质是必需的（Radichev et al. 2006）。ORC(2-5) 复合物表现出紧密的自抑制构象，其中 ORC2 的翼状螺旋结构域（WHD）完全阻塞中央 DNA 结合通道。ORC1 的结合重塑 ORC2 的 WHD，将其移开中央通道并部分解除自抑制（Cheng et al. 2020, Jaremko et al. 2020）。ORC6 与 ORC(1-5) 复合物结合形成 ORC(1-6) 复合物（Ghosh et al. 2011）。ORC6 与 ORC(1-5) 复合物的结合较弱，且经常不与其他 ORC(1-5) 亚基共免疫沉淀。ORC4 是唯一被证明直接结合 ORC6 的 ORC(1-5) 亚基（Radichev et al. 2006）。在梅耶 - 戈林综合征中报告的某些 ORC6 突变被证明干扰 ORC6 的整合入 ORC（Balasov et al. 2015）。
大多数人类复制原点包含富含鸟嘌呤（G）的序列，可能形成 G-四链体（G4）结构（Besnard et al. 2012），这些 G4 结构可能介导 ORC1 对复制原点的识别（Hoshina et al. 2013; Eladl et al. 2021）。除了结合无核小体复制原点 DNA 外，ORC1 还与相邻的核小体相互作用（Hizume et al. 2013），特别是富含 H4 二聚体在赖氨酸 21 甲基化（H4K20me2 标记）的核小体，该标记在复制原点中富集。ORC1 结合 H4K20me2 促进 ORC1 结合复制原点及 ORC 染色质加载（Kuo et al. 2012, Zhang et al. 2015）。
ORC1 结合位点普遍与编码和非编码 RNA 的转录起始位点（TSS）相关联。与中等至高转录水平的 TSS 相关的复制原点（属于编码 RNA）在早期 S 期启动，而与低转录水平的 TSS 相关的复制原点（属于非编码 RNA）在整个 S 期启动（Dellino et al. 2013）。
ORC2 与 ORC3 形成异二聚体，这是 ORC5 及随后 ORC4 结合的前提条件（Ranjan and Gossen 2006; Siddiqui and Stillman 2007）。ORC1 与核内的 ORC(2-5) 复合物结合形成稳定的 ORC(1-5) 复合物（Radichev et al. 2006; Ghosh et al. 2011）。ORC1 对于 ORC(2-5) 复合物结合染色质是必需的（Radichev et al. 2006）。ORC(2-5) 复合物表现出紧密的自抑制构象，其中 ORC2 的翼状螺旋结构域（WHD）完全阻塞中央 DNA 结合通道。ORC1 的结合重塑 ORC2 的 WHD，将其移开中央通道并部分解除自抑制（Cheng et al. 2020, Jaremko et al. 2020）。ORC6 与 ORC(1-5) 复合物结合形成 ORC(1-6) 复合物（Ghosh et al. 2011）。ORC6 与 ORC(1-5) 复合物的结合较弱，且经常不与其他 ORC(1-5) 亚基共免疫沉淀。ORC4 是唯一被证明直接结合 ORC6 的 ORC(1-5) 亚基（Radichev et al. 2006）。在梅耶 - 戈林综合征中报告的某些 ORC6 突变被证明干扰 ORC6 的整合入 ORC（Balasov et al. 2015）。
英文描述
Assembly of the ORC complex at the origin of replication Human ORC1 can associate with DNA origin of replication sites independently of other origin of replication complex (ORC) subunits (Hoshina et al. 2013; Eladl et al. 2021). ORC1 localizes to condensed chromosomes during early mitosis (M phase) and serves as a nucleating center for the assembly of the ORC and, subsequently, the pre-replication complex. ORC1 remains associated with late replication origins throughout late G1. Upon S phase entry, ORC1 undergoes ubiquitin-mediated degradation, leading to dissociation of the ORC from chromatin (Kara et al. 2015).
Most human replication origins contain guanine (G)-rich sequences which may form G-quadruplex (G4) structures (Besnard et al. 2012) and these G4 structures may mediate the recognition of replication origins by ORC1 (Hoshina et al. 2013; Eladl et al. 2021). Besides binding to nucleosome-free replication origin DNA, ORC1 interacts with neighboring nucleosomes (Hizume et al. 2013), in particular with nucleosomes containing histone H4 dimethylated at lysine 21 (H4K20me2 mark), which is enriched at replication origins. Binding of ORC1 to H4K20me2 facilitates ORC1 binding to replication origins and ORC chromatin loading (Kuo et al. 2012, Zhang et al. 2015).
ORC1 binding sites are universally associated with transcription start sites (TSSs) of coding and non-coding RNAs. Replication origins associated with moderate to high transcription level TSSs (belonging to coding RNAs) fire in early S phase, while those associated with low transcription level TSSs (belonging to non-coding RNAs) fire throughout the S phase (Dellino et al. 2013).
ORC2 forms a heterodimer with ORC3, which is a prerequisite for the association of ORC5 and, subsequently, ORC4 (Ranjan and Gossen 2006; Siddiqui and Stillman 2007). ORC1 binds to the ORC(2-5) complex in the nucleus to form a stable ORC(1-5) complex (Radichev et al. 2006; Ghosh et al. 2011). ORC1 is necessary for the association of the ORC(2-5) complex to chromatin (Radichev et al. 2006). The ORC(2-5) complex exhibits a tightly autoinhibited conformation, with the winged-helix domain (WHD) of ORC2 completely blocking the central DNA-binding channel. Binding of ORC1 remodels the WHD of ORC2, moving it away from the central channel and partially relieving the autoinhibition (Cheng et al. 2020, Jaremko et al. 2020). ORC6 associates with the ORC(1-5) complex to form the ORC(1-6) complex (Ghosh et al. 2011). The association of ORC6 with the ORC(1-5) complex is weak and it frequently does not co-immunoprecipitate with the other ORC(1-5) subunits. ORC4 is the only ORC(1-5) subunit that was shown to directly bind to ORC6 (Radichev et al. 2006). Some ORC6 mutations reported in Meier-Gorlin syndrome were shown to interfere with ORC6 incorporation into the ORC (Balasov et al. 2015).
Most human replication origins contain guanine (G)-rich sequences which may form G-quadruplex (G4) structures (Besnard et al. 2012) and these G4 structures may mediate the recognition of replication origins by ORC1 (Hoshina et al. 2013; Eladl et al. 2021). Besides binding to nucleosome-free replication origin DNA, ORC1 interacts with neighboring nucleosomes (Hizume et al. 2013), in particular with nucleosomes containing histone H4 dimethylated at lysine 21 (H4K20me2 mark), which is enriched at replication origins. Binding of ORC1 to H4K20me2 facilitates ORC1 binding to replication origins and ORC chromatin loading (Kuo et al. 2012, Zhang et al. 2015).
ORC1 binding sites are universally associated with transcription start sites (TSSs) of coding and non-coding RNAs. Replication origins associated with moderate to high transcription level TSSs (belonging to coding RNAs) fire in early S phase, while those associated with low transcription level TSSs (belonging to non-coding RNAs) fire throughout the S phase (Dellino et al. 2013).
ORC2 forms a heterodimer with ORC3, which is a prerequisite for the association of ORC5 and, subsequently, ORC4 (Ranjan and Gossen 2006; Siddiqui and Stillman 2007). ORC1 binds to the ORC(2-5) complex in the nucleus to form a stable ORC(1-5) complex (Radichev et al. 2006; Ghosh et al. 2011). ORC1 is necessary for the association of the ORC(2-5) complex to chromatin (Radichev et al. 2006). The ORC(2-5) complex exhibits a tightly autoinhibited conformation, with the winged-helix domain (WHD) of ORC2 completely blocking the central DNA-binding channel. Binding of ORC1 remodels the WHD of ORC2, moving it away from the central channel and partially relieving the autoinhibition (Cheng et al. 2020, Jaremko et al. 2020). ORC6 associates with the ORC(1-5) complex to form the ORC(1-6) complex (Ghosh et al. 2011). The association of ORC6 with the ORC(1-5) complex is weak and it frequently does not co-immunoprecipitate with the other ORC(1-5) subunits. ORC4 is the only ORC(1-5) subunit that was shown to directly bind to ORC6 (Radichev et al. 2006). Some ORC6 mutations reported in Meier-Gorlin syndrome were shown to interfere with ORC6 incorporation into the ORC (Balasov et al. 2015).
所含基因
36 个基因