A conserved mechanism for regulating replisome disassembly in eukaryotes

Jenkyn-Bedford, Michael; Jones, Morgan L.; Baris, Yasemin; Labib, Karim; Cannone, Giuseppe; Yeeles, Joseph T.P.; Deegan, Tom

doi:10.1038/s41586-021-04145-3

Cited by 70 publications

(68 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although a recombinant MCM2–7 hexamer has successfully been reconstructed using an overexpression system based on yeast, insect, and human cells ( Jenkyn-Bedford et al, 2021 ; Rzechorzek et al, 2020 ; Yeeles et al, 2015 ), little is known about how the MCM2–7 hexamer is assembled in living cells. In this study, we revealed that MCMBP played a crucial role in the assembly of the MCM2–7 hexamer in human cells.…”

Section: Discussionmentioning

confidence: 99%

MCMBP promotes the assembly of the MCM2–7 hetero-hexamer to ensure robust DNA replication in human cells

Saito

Santosa

Ishiguro

et al. 2022

eLife

View full text Add to dashboard Cite

The MCM2–7 hetero-hexamer is the replicative DNA helicase that plays a central role in eukaryotic DNA replication. In proliferating cells, the expression level of the MCM2–7 hexamer is kept high, which safeguards the integrity of the genome. However, how the MCM2–7 hexamer is assembled in living cells remains unknown. Here, we revealed that the MCM-binding protein (MCMBP) plays a critical role in the assembly of this hexamer in human cells. MCMBP associates with MCM3 which is essential for maintaining the level of the MCM2–7 hexamer. Acute depletion of MCMBP demonstrated that it contributes to MCM2–7 assembly using nascent MCM3. Cells depleted of MCMBP gradually ceased to proliferate because of reduced replication licensing. Under this condition, p53-positive cells exhibited arrest in the G1 phase, whereas p53-null cells entered the S phase and lost their viability because of the accumulation of DNA damage, suggesting that MCMBP is a potential target for killing p53-deficient cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

MCMBP promotes the assembly of the MCM2–7 hetero-hexamer to ensure robust DNA replication in human cells

Saito

Santosa

Ishiguro

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…This inhibition was mediated by replication fork DNA. Recent study ( Jenkyn-Bedford et al, 2021 ) could have shown that the leucine rich repeat domains of Dia2 and LRR1 are different in structure, but bind to a common site on CMG, including MCM3 and MCM5 zinc finger domains, and LRR-MCM interaction was crucial for the decomposition of replicas, and it is crucial that it is duplicated to exclude DNA chain closure, which lay a structural foundation for inhibiting CMG ubiquitination before termination. Down regulated expression in three negative breast cancer could affect prognosis and chemotherapy sensitivity ( Sheng et al, 2021 ), which could also be seen in other cancers ( Lu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

DNA Damage Repair-Related Genes Signature for Immune Infiltration and Outcome in Cervical Cancer

Wang

Sun

2022

Front. Genet.

View full text Add to dashboard Cite

Background: The mechanism of DNA damage repair plays an important role in many solid tumors represented by cervical cancer.Purpose: The purpose of this study was to explore the effect of DNA damage repair-related genes on immune function of patients with cervical cancer, and to establish and evaluate a prognosis model based on DNA damage repair-related genes.Methods: In the study, we analyzed the genes related to DNA damage and repair, and obtained two subtypes (F1 and F2). We selected two groups of samples for different selection, and studied which pathways were enriched expression. For different subtypes, the immune score was explored to explain immune infiltration. We got the key genes through screening, and established the prognosis model through the key genes. These 11 key genes were correlated with the expression of common Clusters of Differentiation (CD) genes in order to explore the effects of these genes on immunity.Results: Through the Least absolute shrinkage and selection operator (LASSO) method, we screened 11 genes from 232 candidate genes as the key genes for the prognosis score. Through the Kaplan-Meier method, four genes (HAP1, MCM5, RNASEH2A, CETN2) with significant prognostic significance were screened into the final model, forming a Nomogram with C-index of 0.716 (0.649–1.0).Conclusion: In cervical cancer, DNA damage repair related genes and immune cell infection characteristics have certain association, and DNA damage repair related genes and immune cell infection characteristics can effectively predict the prognosis.

show abstract

“…Assembly of two CMGs at an origin disrupts the double hexamer interface 1 . Mapping the relative orientation of the two separated CMGs on the origin DNA is important to understand how replication forks are established bidirectionally and how replisome stability is maintained in the early stages of replication initiation 17 – 22 .…”

Section: Mainmentioning

confidence: 99%

Mechanism of replication origin melting nucleated by CMG helicase assembly

Lewis

Gross

Sousa

et al. 2022

Nature

View full text Add to dashboard Cite

The activation of eukaryotic origins of replication occurs in temporally separated steps to ensure that chromosomes are copied only once per cell cycle. First, the MCM helicase is loaded onto duplex DNA as an inactive double hexamer. Activation occurs after the recruitment of a set of firing factors that assemble two Cdc45–MCM–GINS (CMG) holo-helicases. CMG formation leads to the underwinding of DNA on the path to the establishment of the replication fork, but whether DNA becomes melted at this stage is unknown1. Here we use cryo-electron microscopy to image ATP-dependent CMG assembly on a chromatinized origin, reconstituted in vitro with purified yeast proteins. We find that CMG formation disrupts the double hexamer interface and thereby exposes duplex DNA in between the two CMGs. The two helicases remain tethered, which gives rise to a splayed dimer, with implications for origin activation and replisome integrity. Inside each MCM ring, the double helix becomes untwisted and base pairing is broken. This comes as the result of ATP-triggered conformational changes in MCM that involve DNA stretching and protein-mediated stabilization of three orphan bases. Mcm2 pore-loop residues that engage DNA in our structure are dispensable for double hexamer loading and CMG formation, but are essential to untwist the DNA and promote replication. Our results explain how ATP binding nucleates origin DNA melting by the CMG and maintains replisome stability at initiation.

show abstract

A conserved mechanism for regulating replisome disassembly in eukaryotes

Cited by 70 publications

References 41 publications

MCMBP promotes the assembly of the MCM2–7 hetero-hexamer to ensure robust DNA replication in human cells

MCMBP promotes the assembly of the MCM2–7 hetero-hexamer to ensure robust DNA replication in human cells

DNA Damage Repair-Related Genes Signature for Immune Infiltration and Outcome in Cervical Cancer

Mechanism of replication origin melting nucleated by CMG helicase assembly

Contact Info

Product

Resources

About