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Comment
. 2022 Feb 9:11:e76475.
doi: 10.7554/eLife.76475.

The remarkable gymnastics of ORC

Bruce Stillman  1
Affiliations
Comment

The remarkable gymnastics of ORC

Bruce Stillman. Elife. .

Abstract

As a cell prepares to divide, a molecular actor known as the Origin Recognition Complex makes intricate ATP-driven movements to recruit proteins required to duplicate DNA.

Keywords: Cdt1; Mcm2-7; ORC; S. cerevisiae; biochemistry; chemical biology; chromosomes; gene expression; helicase; origin licensing; replication.

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Conflict of interest statement

BS No competing interests declared

Figures

Figure 1.
Figure 1.. The assembly of the pre-replicative complex requires a seven-step process which involves ORC ‘flipping’ over the Mcm2-7 complex.
(A) The genetic sequence which acts as the starting point for replication in S. cerevisiae (DNA segment in orange) consists of four elements (black segments), with the A and B2 elements binding ORC in opposite orientations. (B) ORC (lime green, Orc6 yellow) first binds to the A and B1 elements. (C) ORC recruits Cdc6 (green). (D) ORC-Cdc6 recruits the Cdt1-Mcm2-7 complex (Cdt1, blue and Mcm2-7 light blue; Mcm2 and Mcm5 are parts of the six proteins in the complex) so that the DNA is aligned to a channel in the Mcm2-7 hexamer. The Mcm2-7 complex is oriented based on the structure of the protein components; with a C-terminus (or extremity; Mcm-C or ‘C’) at one end, and an N-terminus (Mcm-N or ‘N’) at the other. At this stage, Mcm-C binds ORC-Cdc6. (E) The double stranded DNA is inserted into the channel between the Mcm2 and Mcm5 subunits in the Mcm2-7 hexamer and the hexamer is partially closed, to create an intermediary known as the OCCM. (F) ATP hydrolysis by the Mcm2-7 expels the first Cdc6 and then Cdt1 to create the OM complex. (G) ORC flips to the other side of Mcm2-7 and presumably binds to the B2 element, creating the MO complex. As a result, the ORC subunit Orc6 is now orientated towards Mcm2-7-N. (H) ORC can now recruit a second Cdc6, creating a binding site for a second Cdt1-Mcm2-7 complex that is loaded in an opposite orientation to the first Mcm2-7. The Mcm2-7 double hexamer, possibly with ORC still bound to the DNA, establishes the pre-replicative complex that is a precursor for the activation of two enzymes that will unwind the DNA helix when the cell is ready to divide.
See this image and copyright information in PMC

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References

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