Xenopus Mcm10 is a CDK-substrate required for replication fork stability

Chadha, Gaganmeet Singh; Gambus, Agnieszka; Gillespie, Peter J.; Blow, J. Julian

doi:10.1080/15384101.2016.1199305

Cited by 27 publications

(46 citation statements)

References 68 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1 A). Among genes whose KO selectively impaired proliferation of ETAA1Δ cells, we identified several factors with known roles in promoting DNA synthesis, including MCM10, POLE3, POLE4, and CDC25A (Bartek et al, 2004;Chadha et al, 2016;Bellelli et al, 2018), while sgRNAs targeting essential DNA replication factors including proliferating cell nuclear antigen and CMG helicase subunits were depleted in both WT and ETAA1Δ cells as expected (Fig. 1, B and C; Fig.…”

Section: Resultssupporting

confidence: 77%

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Achuthankutty

Thakur

Haahr

et al. 2019

Journal of Cell Biology

View full text Add to dashboard Cite

The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9–based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle– and replication stress–dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

show abstract

Section: Resultssupporting

confidence: 77%

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Achuthankutty

Thakur

Haahr

et al. 2019

Journal of Cell Biology

View full text Add to dashboard Cite

show abstract

“…MCM10 reportedly plays a role in tethering DNA polymerase α at the replication origin and forks. Studies using Xenopus egg extracts indicated that Mcm10 plays an essential role as a scaffold in the progression of the DNA replication fork by tethering replication proteins, and phosphorylation of Mcm10 at S630 with CDK is involved in protein assembly at the fork (Chadha et al, 2016). In elongation during DNA replication, Mcm10 is required for gene silencing and chromosomal condensation (Apger et al, 2010).…”

Section: Muta�onmentioning

confidence: 99%

Regulation of MCM2-7 function

Ishimi

2018

Genes Genet. Syst.

View full text Add to dashboard Cite

Recently published structural and functional analyses of the CMG complex have provided insight into the mechanism of its DNA helicase function and into the distinct roles of its central six component proteins MCM2-MCM7 (MCM2-7). To activate CMG helicase, the two protein kinases CDK and DDK, as well as MCM10, are required. In addition to the initiation of DNA replication, MCM function must be regulated at the DNA replication steps of elongation and termination. Polyubiquitylation of MCM7 is involved in terminating MCM function. Reinitiation of DNA replication in a single cell cycle, which is prevented mainly by CDK, is understood at the molecular level. MCM2-7 gene expression is regulated during cellular aging and the cell cycle, and the expression depends on oxygen concentration. These regulatory processes have been described recently. Genomic structural alteration, which is an essential element in cancer progression, is mainly generated by disruptions of DNA replication fork structures. A point mutation in MCM4 that disturbs MCM2-7 function results in genomic instability, leading to the generation of cancer cells. In this review, I focus on the following points: 1) function of the MCM2-7 complex, 2) activation of MCM2-7 helicase, 3) regulation of MCM2-7 function, 4) MCM2-7 expression, and 5) the role of MCM mutation in cancer progression.

show abstract

“…Furthermore, recruitment of Mcm10 is dependent on Cdc45, GINS, DDK, and S-CDK (7,8). Recent results obtained in a Xenopus egg extract system also support that chromatin loading of Mcm10 requires DDK and S-CDK (45).…”

mentioning

confidence: 58%

The Mcm2–7-interacting domain of human mini-chromosome maintenance 10 (Mcm10) protein is important for stable chromatin association and origin firing

Izumi

Mizuno

Yanagi

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

The protein mini-chromosome maintenance 10 (Mcm10) was originally identified as an essential yeast protein in the maintenance of mini-chromosome plasmids. Subsequently, Mcm10 has been shown to be required for both initiation and elongation during chromosomal DNA replication. However, it is not fully understood how the multiple functions of Mcm10 are coordinated or how Mcm10 interacts with other factors at replication forks. Here, we identified and characterized the Mcm2-7-interacting domain in human Mcm10. The interaction with Mcm2-7 required the Mcm10 domain that contained amino acids 530-655, which overlapped with the domain required for the stable retention of Mcm10 on chromatin. Expression of truncated Mcm10 in HeLa cells depleted of endogenous Mcm10 via siRNA revealed that the Mcm10 conserved domain (amino acids 200-482) is essential for DNA replication, whereas both the conserved and the Mcm2-7-binding domains were required for its full activity. Mcm10 depletion reduced the initiation frequency of DNA replication and interfered with chromatin loading of replication protein A, DNA polymerase (Pol) α, and proliferating cell nuclear antigen, whereas the chromatin loading of Cdc45 and Pol ϵ was unaffected. These results suggest that human Mcm10 is bound to chromatin through the interaction with Mcm2-7 and is primarily involved in the initiation of DNA replication after loading of Cdc45 and Pol ϵ.

show abstract

Xenopus Mcm10 is a CDK-substrate required for replication fork stability

Cited by 27 publications

References 68 publications

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Regulation of MCM2-7 function

The Mcm2–7-interacting domain of human mini-chromosome maintenance 10 (Mcm10) protein is important for stable chromatin association and origin firing

Contact Info

Product

Resources

About