Switch on the engine: how the eukaryotic replicative helicase MCM2–7 becomes activated

Abstract

A crucial step during eukaryotic initiation of DNA replication is the correct loading and activation of the replicative DNA helicase, which ensures that each replication origin fires only once. Unregulated DNA helicase loading and activation, as it occurs in cancer, can cause severe DNA damage and genomic instability. The essential mini-chromosome maintenance proteins 2-7 (MCM2-7) represent the core of the eukaryotic replicative helicase that is loaded at DNA replication origins during G1-phase of the cell cycle. The MCM2-7 helicase activity, however, is only triggered during S-phase once the holo-helicase Cdc45-MCM2-7-GINS (CMG) has been formed. A large number of factors and several kinases interact and contribute to CMG formation and helicase activation, though the exact mechanisms remain unclear. Crucially, upon DNA damage, this reaction is temporarily halted to ensure genome integrity. Here, we review the current understanding of helicase activation;we focus on protein interactions during CMG formation, discuss structural changes during helicase activation and outline similarities and differences of the prokaryotic and eukaryotic helicase activation process.3

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

“…33 MCMs are essential factors for eukaryotic DNA replication.Of them, MCM2 is highly expressed in both proliferative and transformational phase and is considered a proliferative marker. 34,35 Of the other changed genes in CPZ-treated mice, HUS1 and Chk1 encode components of cell cycle checkpoint complex able to cause cell cycle arrest in response to DNA repair and cell death thus preventing damaged cells from progressing through the cell cycle. [36][37][38] Ddit 3 (also referred to Gadd153, Chop) is a DNA damage-inducible transcript 3 protein.…”

Insights into the Initiation of Eukaryotic DNA Replication

“…Since the parental duplex is double-stranded, the replication fork helicase is required to melt the parental duplex to form single DNA strands (ssDNA). 6 The replication fork helicase therefore functions before the replicative polymerases, and therefore the replication fork helicase is the physiologic target for cell cycle regulation. 6 The Replication Fork Helicase is CMG dpb11-1 (DNA-polymerase B-interacting protein)], Psf1 (partner with Sld5), Psf2, Psf3).…”

“…6 The replication fork helicase therefore functions before the replicative polymerases, and therefore the replication fork helicase is the physiologic target for cell cycle regulation. 6 The Replication Fork Helicase is CMG dpb11-1 (DNA-polymerase B-interacting protein)], Psf1 (partner with Sld5), Psf2, Psf3). 7 The Mcm2-7 heterohexameric ring complex is the motor of the CMG helicase.…”

“…6 Moreover, CMG complex formation is also regulated in budding yeast by 4 initiationspecific protein factors, Sld2 (RecQL4 or RecQ4 in humans), Sld3 (Treslin or TICRR in humans), Sld7, and Dpb11 (TopBP1 in humans). 6 These factors do not travel as part of the CMG active helicase.…”

“…6 Moreover, CMG complex formation is also regulated in budding yeast by 4 initiationspecific protein factors, Sld2 (RecQL4 or RecQ4 in humans), Sld3 (Treslin or TICRR in humans), Sld7, and Dpb11 (TopBP1 in humans). 6 These factors do not travel as part of the CMG active helicase. 22 S-CDK plays also an important role in inhibiting the Mcm2-7 loading reaction during S phase, allowing licensing to take place only during G 1 .…”