ORC1 binds to DNA at origin of replication sites

Stable Identifier
Reaction [binding]
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). Most human replication origins contain guanine (G)-rich sequences which may form G-quadruplex (G4) structures (Besnard et al. 2012). The region of human ORC1 involving amino acids 413-511 preferentially binds to G4 structures in the DNA over double-stranded DNA. G4 structures are retained even after ORC1 binding, suggesting that they may mediate 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). The interaction of ORC1 with nucleosomes may require specific epigenetic marks on nucleosomes, and may be disrupted by ORC1 mutations associated with the Meier-Gorlin Syndrome (Zhang et al. 2015). In particular, a bromo adjacent homology (BAH) domain of ORC1 has been shown to bind to 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).

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).

Literature References
PubMed ID Title Journal Year
25784553 Orc1 Binding to Mitotic Chromosomes Precedes Spatial Patterning during G1 Phase and Assembly of the Origin Recognition Complex in Human Cells

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

J Biol Chem 2015
22751019 Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs

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

Nat Struct Mol Biol 2012
23187890 Genome-wide mapping of human DNA-replication origins: levels of transcription at ORC1 sites regulate origin selection and replication timing

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

Genome Res 2013
25689043 A Meier-Gorlin syndrome mutation impairs the ORC1-nucleosome association

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

ACS Chem Biol 2015
33801762 Investigation of the Interaction of Human Origin Recognition Complex Subunit 1 with G-Quadruplex DNAs of Human c-myc Promoter and Telomere Regions

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

Int J Mol Sci 2021
23795651 Concerted interaction between origin recognition complex (ORC), nucleosomes and replication origin DNA ensures stable ORC-origin binding

Hizume, K, Yagura, M, Araki, H

Genes Cells 2013
24003239 Human origin recognition complex binds preferentially to G-quadruplex-preferable RNA and single-stranded DNA

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

J Biol Chem 2013
22398447 The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome

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

Nature 2012
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