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The dynamic nature of the human origin recognition complex revealed through five cryoEM structures.

<div class='caption-title'>Overall architecture of human ORC.</div>
<div class='caption-title'>ATP sites of each ORC conformation.</div>
<div class='caption-title'>CryoEM workflow of ORC1-5.</div>
Jaremko MJ, On KF, Thomas DR, Stillman B, Joshua-Tor L
OpenAccess logo Elife 9 (2020)
Related entries: 7jpo, 7jpp, 7jpr, 7jps

Cited: 13 times
EuropePMC logo PMID: 32808929

Abstract

Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. The absence of ORC1 revealed a compact, stable complex of ORC2-5. Introduction of ORC1 opens the complex into several dynamic conformations. Two structures revealed dynamic movements of the ORC1 AAA+ and ORC2 winged-helix domains that likely impact DNA incorporation into the ORC core. Additional twist and pinch motions were observed in an open ORC conformation revealing a hinge at the ORC5·ORC3 interface that may facilitate ORC binding to DNA. Finally, a structure of ORC was determined with endogenous DNA bound in the core revealing important differences between human and yeast origin recognition.

Reviews citing this publication (4)

  1. Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms. Schmit M, Bielinsky AK. Int J Mol Sci 22 E911 (2021)
  2. Read, Write, Adapt: Challenges and Opportunities during Kinetoplastid Genome Replication. Damasceno JD, Marques CA, Black J, Briggs E, McCulloch R. Trends Genet 37 21-34 (2021)
  3. Exploring the Structural Variability of Dynamic Biological Complexes by Single-Particle Cryo-Electron Microscopy. DiIorio MC, Kulczyk AW. Micromachines (Basel) 14 118 (2022)
  4. The Adaptive Mechanisms and Checkpoint Responses to a Stressed DNA Replication Fork. Saldanha J, Rageul J, Patel JA, Kim H. Int J Mol Sci 24 10488 (2023)

Articles citing this publication (9)

  1. Multiple, short protein binding motifs in ORC1 and CDC6 control the initiation of DNA replication. Hossain M, Bhalla K, Stillman B. Mol Cell 81 1951-1969.e6 (2021)
  2. The structure of ORC-Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6. Feng X, Noguchi Y, Barbon M, Stillman B, Speck C, Li H. Nat Commun 12 3883 (2021)
  3. Mobile origin-licensing factors confer resistance to conflicts with RNA polymerase. Scherr MJ, Wahab SA, Remus D, Duderstadt KE. Cell Rep 38 110531 (2022)
  4. Establishment and function of chromatin organization at replication origins. Chacin E, Reusswig KU, Furtmeier J, Bansal P, Karl LA, Pfander B, Straub T, Korber P, Kurat CF. Nature 616 836-842 (2023)
  5. The human origin recognition complex is essential for pre-RC assembly, mitosis, and maintenance of nuclear structure. Chou HC, Bhalla K, Demerdesh OE, Klingbeil O, Hanington K, Aganezov S, Andrews P, Alsudani H, Chang K, Vakoc CR, Schatz MC, McCombie WR, Stillman B. Elife 10 e61797 (2021)
  6. A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6. Schmidt JM, Yang R, Kumar A, Hunker O, Seebacher J, Bleichert F. Nat Commun 13 1059 (2022)
  7. A dual role for the chromatin reader ORCA/LRWD1 in targeting the origin recognition complex to chromatin. Sahu S, Ekundayo BE, Kumar A, Bleichert F. EMBO J 42 e114654 (2023)
  8. 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 22 3481 (2021)
  9. ORChestra coordinates the replication and repair music. Liu D, Sonalkar J, Prasanth SG. Bioessays 45 e2200229 (2023)


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