Dear Colleagues,

The reconstitution of eukaryotic DNA replication in vitro, together with the great advances in our structural understanding of the many discrete steps required for DNA replication initiation afforded by the advent of increasingly higher resolution cryo-EM, have provided us with a far greater understanding of the eukaryotic DNA replication process than we could ever have envisaged just a decade ago.

The MCM (MiniChromosome Maintenance) proteins were first identified in budding yeast almost 40 years ago. The key to genome duplication in eukaryotes is the MCM2-7 heterohexamer: MCM2-7 forms the core of the CMG replicative helicase that unwinds DNA during the S phase to facilitate its replication.

MCM2-7 is first loaded onto chromatin as an inactive double hexamer at the sites of potential replication initiation, referred to as replication origins, during the late M and G1 phases; this MCM2-7 loading 'licenses' an origin to support one round of replication initiation in the upcoming S phase. The loading of MCM2-7 onto replication origins, a process known as 'replication licensing', requires three additional factors: ORC—the origin recognition complex, CDC6, and CDT1. Further to replication licensing, each of these factors play additional roles in the control of cell cycle progression, in processes as diverse as transcriptional regulation, the establishment of chromatid cohesion, kinetochore formation, and cytokinesis. During the S phase the MCM2-7 double hexamers are split and activated to form the CMG replicative helicase and following replication initiation CMG facilitates replication elongation as part of the replication fork. Upon replication termination, MCM2-7 proteins are removed from chromatin in a ubiquitylation-dependent manner. This dynamic association of MCM2-7 with chromatin once per cell cycle controls genome duplication and thus contributes to the maintenance of genomic stability.

The mutation or misregulation of the replication licensing proteins can generate replication stress, which results in genomic instability and has been indicated in the aetiology of human diseases: the development of cancer and the developmental disorder Meier–Gorlin Syndrome. Pharmacological intervention targeted at the replication licensing system may therefore be of considerable interest in ameliorating these disease states. Of particular interest is the distinct response of cancer and somatic cells to the inhibition of replication licensing.

In this Special Issue, to provide a complete description of the role of the replication licensing factors during the eukaryotic cell cycle, we encourage the submission of manuscripts covering all aspects of the replication licensing system, from the initiation of DNA replication, through the non-licensing roles of the replication licensing factors, to the discussion of the role of the misregulation of the replication licensing system in disease and the potential for the development of therapeutic intervention.

Dr. Peter J. Gillespie
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• cell cycle
• DNA replication
• genome stability
• replication licensing
• MCM2-7
• ORC
• Cdc6
• CDT1
• cancer
• Meier-Gorlin syndrome