Editing DNA replication (section)

=== Pre-replication complex ===
{{Main|Pre-replication complex}}

In late [[mitosis]] and early [[G1 phase]], a large complex of initiator proteins assembles into the pre-replication complex at particular points in the DNA, known as "[[origin of replication|origins]]".<ref name="origins" /><ref name="Hu 352–372" /> In ''[[Escherichia coli|E. coli]]'' the primary initiator protein is [[DnaA|Dna A]]; in [[yeast]], this is the [[origin recognition complex]].<ref>{{Cite journal |vauthors=Weigel C, Schmidt A, Rückert B, Lurz R, Messer W |date=November 1997 |title=DnaA protein binding to individual DnaA boxes in the Escherichia coli replication origin, oriC |journal=The EMBO Journal |volume=16 |issue=21 |pages=6574–6583 |doi=10.1093/emboj/16.21.6574 |pmc=1170261 |pmid=9351837}}</ref>  Sequences used by initiator proteins tend to be "AT-rich" (rich in adenine and thymine bases), because A-T base pairs have two hydrogen bonds (rather than the three formed in a C-G pair) and thus are easier to strand-separate.<ref>{{Cite book |url=https://archive.org/details/molecularcellbio00lodi |title=Molecular Cell Biology |vauthors=Lodish H, Berk A, Zipursky LS, Matsudaira P, Baltimore D, Darnell J |publisher=W. H. Freeman and Company |year=2000 |isbn=0-7167-3136-3}}[https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.section.3163#3179 12.1.  General Features of Chromosomal Replication: Three Common Features of Replication Origins]</ref>  In eukaryotes, the origin recognition complex catalyzes the assembly of initiator proteins into the pre-replication complex. In addition, a recent report suggests that budding yeast ORC dimerizes in a cell cycle dependent manner to control licensing.<ref>{{Cite journal |vauthors=Lin YC, Prasanth SG |date=July 2021 |title=Replication initiation: Implications in genome integrity |journal=DNA Repair |volume=103 |page=103131 |doi=10.1016/j.dnarep.2021.103131 |pmc=8296962 |pmid=33992866 |doi-access=free}}</ref><ref>{{Cite journal |display-authors=6 |vauthors=Amin A, Wu R, Cheung MH, Scott JF, Wang Z, Zhou Z, Liu C, Zhu G, Wong CK, Yu Z, Liang C |date=March 2020 |title=An Essential and Cell-Cycle-Dependent ORC Dimerization Cycle Regulates Eukaryotic Chromosomal DNA Replication |journal=Cell Reports |volume=30 |issue=10 |pages=3323–3338.e6 |doi=10.1016/j.celrep.2020.02.046 |pmid=32160540 |doi-access=free}}</ref> In turn, the process of ORC dimerization is mediated by a cell cycle-dependent Noc3p dimerization cycle in vivo, and this role of Noc3p is separable from its role in ribosome biogenesis. [https://www.life-science-alliance.org/content/6/3/e202201594.full An essential Noc3p dimerization cycle mediates ORC double-hexamer formation in replication licensing] ORC and Noc3p are continuously bound to the chromatin throughout the cell cycle.<ref>{{Cite journal |vauthors=Zhang Y, Yu Z, Fu X, Liang C |date=June 2002 |title=Noc3p, a bHLH protein, plays an integral role in the initiation of DNA replication in budding yeast |journal=Cell |volume=109 |issue=7 |pages=849–860 |doi=10.1016/s0092-8674(02)00805-x |pmid=12110182 |doi-access=free}}</ref>  [[CDC6|Cdc6]] and [[DNA replication factor CDT1|Cdt1]] then associate with the bound origin recognition complex at the origin in order to form a larger complex necessary to load the [[Minichromosome maintenance|Mcm complex]] onto the DNA. In eukaryotes, the Mcm complex is the helicase that will split the DNA helix at the replication forks and origins. The Mcm complex is recruited at late G1 phase and loaded by the ORC-Cdc6-Cdt1 complex onto the DNA via ATP-dependent protein remodeling. The loading of the MCM complex onto the origin DNA marks the completion of pre-replication complex formation.<ref name="Morgan-2007">{{Cite book |title=The cell cycle: principles of control |vauthors=Morgan DO |date=2007 |publisher=New Science Press |isbn=978-0-19-920610-0 |location=London |pages=64–75 |oclc=70173205}}</ref>

If environmental conditions are right in late G1 phase, the G1 and G1/S [[cyclin]]-[[Cyclin-dependent kinase|Cdk]] complexes are activated, which stimulate expression of genes that encode components of the DNA synthetic machinery. G1/S-Cdk activation also promotes the expression and activation of S-Cdk complexes, which may play a role in activating replication origins depending on species and cell type. Control of these Cdks vary depending on cell type and stage of development. This regulation is best understood in [[budding yeast]], where the S cyclins [[Clb 5,6 (Cdk1)|Clb5]] and [[Clb 5,6 (Cdk1)|Clb6]] are primarily responsible for DNA replication.<ref>{{Cite journal |vauthors=Donaldson AD, Raghuraman MK, Friedman KL, Cross FR, Brewer BJ, Fangman WL |date=August 1998 |title=CLB5-dependent activation of late replication origins in S. cerevisiae |journal=Molecular Cell |volume=2 |issue=2 |pages=173–182 |doi=10.1016/s1097-2765(00)80127-6 |pmid=9734354 |doi-access=free}}</ref> Clb5,6-Cdk1 complexes directly trigger the activation of replication origins and are therefore required throughout S phase to directly activate each origin.<ref name="Morgan-2007" />

In a similar manner, [[Cell division cycle 7-related protein kinase|Cdc7]] is also required through [[S phase]] to activate replication origins. Cdc7 is not active throughout the cell cycle, and its activation is strictly timed to avoid premature initiation of DNA replication. In late G1, Cdc7 activity rises abruptly as a result of association with the regulatory subunit [[DBF4]], which binds Cdc7 directly and promotes its protein kinase activity. Cdc7 has been found to be a rate-limiting regulator of origin activity. Together, the G1/S-Cdks and/or S-Cdks and Cdc7 collaborate to directly activate the replication origins, leading to initiation of DNA synthesis.<ref name="Morgan-2007" />