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The dynamics of eukaryotic replication initiation: origin specificity, licensing,
and firing at the single-molecule level
#MMPMID25921072
Duzdevich D
; Warner MD
; Ticau S
; Ivica NA
; Bell SP
; Greene EC
Mol Cell
2015[May]; 58
(3
): 483-94
PMID25921072
show ga
Eukaryotic replication initiation is highly regulated and dynamic. It begins with
the origin recognition complex (ORC) binding DNA sites called origins of
replication. ORC, together with Cdc6 and Cdt1, mediate pre-replicative complex
(pre-RC) assembly by loading a double hexamer of Mcm2-7: the core of the
replicative helicase. Here, we use single-molecule imaging to directly visualize
Saccharomyces cerevisiae pre-RC assembly and replisome firing in real time. We
show that ORC can locate and stably bind origins within large tracts of
non-origin DNA and that Cdc6 drives ordered pre-RC assembly. We further show that
the dynamics of the ORC-Cdc6 interaction dictate Mcm2-7 loading specificity and
that Mcm2-7 double hexamers form preferentially at a native origin sequence.
Finally, we demonstrate that single Mcm2-7 hexamers propagate bidirectionally,
monotonically, and processively as constituents of active replisomes.
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