MCM10

Official Full Name

minichromosome maintenance 10 replication initiation factor

Organism

Homo sapiens

GeneID

55388

Background

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre-RC) and it may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein can interact with MCM2 and MCM6, as well as with the origin recognition protein ORC2. It is regulated by proteolysis and phosphorylation in a cell cycle-dependent manner. Studies of a similar protein in Xenopus suggest that the chromatin binding of this protein at the onset of DNA replication is after pre-RC assembly and before origin unwinding. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

Synonyms

CNA43; DNA43; IMD80; PRO2249;

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Detailed Information

Minichromosome maintenance proteins (Mcms) play an important role in the initial stages of DNA replication in eukaryotic cells. The Mcm protein family is a class of highly conserved proteins with the same central domain. Mcm1 and Mcm10 are not part of this family of proteins, but are functionally similar to the Mcm family of proteins, which also play an important role in the replication of eukaryotic DNA. Mcm10 is a key replication factor found in the S-stage progression-deficient budding yeast. Comparing Mcm10 homologues, they were found to be structurally and functionally conserved, with three common structures, including the N-terminal domain (NTD) and the conserved internal domain (internal domain), ID) and C-terminal domain (CTD).

The role of Mcm10 in The Initiation of Replication

Mcm10 plays a role in the initiation of DNA replication mainly by promoting the unwinding of DNA double helix and triggering the initiation program, but the specific molecular mechanism is still unclear. Mcm10 is an important replication factor involved in the activation of the Cdc45-Mcm2-7-GINS complex (CMG) helicase, which may be related to the ability of Mcm10 to bind single-stranded DNA or double-stranded DNA. Mcm10 itself does not have enzymatic activity. Some studies have shown that Mcm10 can interact with protein factors such as Pol-α and proliferating cell nuclear antigen (PCNA) on the replication fork to support the scaffolding and participate in DNA unwinding and synthesis, thereby promoting DNA elongation.

Figure 1. Model of Mcm10 function. (Langston, et al. 2017）

Mcm10 is loaded onto DNA in the G1 phase after replication initiation "licensing", and promotes helicase activation and DNA polymerase loading at the beginning of S phase. Prior to loading of Mcm10, the functional replication helicase (CMG dimer) is in an inactive state, and then the stimulation by the complex formed by the binding of Mcm10 to CMG induces activation of the helicase. The expression of Mcm10 in human cells is related to the cell cycle. The study found that the Mcm10 mutant was unable to maintain chromosome integrity and showed defects in S-phase development. If Mcm10 is degraded before the start of S phase, the cells will not be able to complete the transition from G1 phase to S phase, and the DNA replication process will not be successfully initiated. All of the above findings suggest that Mcm10 is involved in the cellular activities of S phase.

Mcm10 and Genome Stabilization

Deletion of the cell Mcm10 results in replication stress, which affects the stability of the replication protein on the DNA strand. Mcm10 disruption in mice significantly reduces DNA synthesis and increases DNA damage; in human cells, knockdown of Mcm10 induces DNA damage, G-phase arrest, and apoptosis. Screening of whole-genome small interfering RNA (siRNA) revealed that knockout of Mcm10 resulted in an increase in the early marker γ-H2AX of DNA double-strand breaks (DSBs). In an independent siRNA screening experiment, it was found that in order to cope with DNA damage caused by Mcm10 knockdown, the level of intracellular DSBs repair marker (p53-binding protein 1, 53BP1) was elevated. The above research data shows that Mcm10 is essential for preventing replication stress and DSBs from accumulating.

Genetic analysis of yeast has demonstrated that the Mcm10 mutant relies on the checkpoint signal factor Mec1 (mitosis entry checkpoint 1) and the radiation sensitive factor Rad53 (radiation sensitive 53). In the case of high replication pressure, Rad53 is hyperactivated, hindering the S phase process. The Mcm10 mutant exhibits loss of adaptability after binding to gene mutations such as checkpoint signaling genes and human capillary ataxia-related genes. After Mcm10 injury, its interaction with genes involved in repairing the repetitive replication fork problem Decreased. Moderate Mcm10 deletion in budding yeast mainly leads to defects in the progression of the replication fork, revealing that Mcm10 maintains genome stability in a number of ways.

References:

Douglas, M. E. , & Diffley, J. F. X. . (2016). Recruitment of mcm10 to sites of replication initiation requires direct binding to the minichromosome maintenance (mcm) complex. Journal of Biological Chemistry, 291(11), 5879-5888.
Langston, L. D. , Mayle, R. , Schauer, G. D. , Yurieva, O. , Zhang, D. , & Yao, N. Y. , et al. (2017). Mcm10 promotes rapid isomerization of cmg-dna for replisome bypass of lagging strand dna blocks. eLife,6,(2017-09-03), 6, e29118.
Becker, J. R. , Nguyen, H. D. , Wang, X. , & Bielinsky, A. K. . (2014). Mcm10 deficiency causes defective-replisome-induced mutagenesis and a dependency on error-free postreplicative repair. Cell Cycle, 13(11), 1737-1748.

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