Assembly of the ORC complex at the origin of replication

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Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
24003239 Human origin recognition complex binds preferentially to G-quadruplex-preferable RNA and single-stranded DNA

Yura, K, Tominaga, A, Kadoma, H, Kiyasu, N, Kunichika, T, Obuse, C, Waga, S, Hoshina, S, Nakatsuka, A, Teranishi, H

J Biol Chem 2013
23795651 Concerted interaction between origin recognition complex (ORC), nucleosomes and replication origin DNA ensures stable ORC-origin binding

Araki, H, Yagura, M, Hizume, K

Genes Cells 2013
26139588 Drosophila model of Meier-Gorlin syndrome based on the mutation in a conserved C-Terminal domain of Orc6

Balasov, M, Akhmetova, K, Chesnokov, I

Am J Med Genet A 2015
17716973 ATP-dependent assembly of the human origin recognition complex

Siddiqui, K, Stillman, B

J Biol Chem 2007
25689043 A Meier-Gorlin syndrome mutation impairs the ORC1-nucleosome association

Song, J, Gozani, O, Zhang, W, Sankaran, S

ACS Chem Biol 2015
23187890 Genome-wide mapping of human DNA-replication origins: levels of transcription at ORC1 sites regulate origin selection and replication timing

Dellino, GI, Cesaroni, M, Giacca, M, Segalla, S, Cittaro, D, Banfi, S, Mendoza-Maldonado, R, Piccioni, R, Pelicci, PG, Luzi, L

Genome Res 2013
16762929 Genetic analysis of human Orc2 reveals specific domains that are required in vivo for assembly and nuclear localization of the origin recognition complex

Radichev, I, Zhao, Y, Vassilev, A, Kwon, SW, DePamphilis, ML

J Biol Chem 2006
22398447 The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome

Song, J, Gozani, O, Patel, DJ, Cheung, P, Chen, JK, Yamazoe, S, Ishibe-Murakami, S, Kuo, AJ

Nature 2012
33298899 Structural insight into the assembly and conformational activation of human origin recognition complex

Wang, X, Cheng, J, Gao, N, Zhai, Y, Hu, J, Li, N

Cell Discov 2020
33801762 Investigation of the Interaction of Human Origin Recognition Complex Subunit 1 with G-Quadruplex DNAs of Human c-myc Promoter and Telomere Regions

Horinouchi, H, Katahira, M, Yamaoki, Y, Nagata, T, Waga, S, Hoshina, S, Kondo, K, Eladl, A

Int J Mol Sci 2021
21555516 Assembly of the human origin recognition complex occurs through independent nuclear localization of its components

Ghosh, S, Zhao, Y, Vassilev, AP, Zhang, J, DePamphilis, ML

J Biol Chem 2011
25784553 Orc1 Binding to Mitotic Chromosomes Precedes Spatial Patterning during G1 Phase and Assembly of the Origin Recognition Complex in Human Cells

Hossain, M, Prasanth, SG, Kara, N, Stillman, B

J Biol Chem 2015
32808929 The dynamic nature of the human origin recognition complex revealed through five cryoEM structures

On, KF, Joshua-Tor, L, Thomas, DR, Stillman, B, Jaremko, MJ

Elife 2020
16549788 A structural role for ATP in the formation and stability of the human origin recognition complex

Gossen, M, Ranjan, A

Proc Natl Acad Sci U S A 2006
22751019 Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs

Parrinello, H, Marin, JM, Dantec, C, Besnard, E, Lapasset, L, Milhavet, O, Babled, A, Lemaitre, JM

Nat Struct Mol Biol 2012
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