A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice

Shima, Naoko; Alcaraz, Ana; Liachko, Ivan; Buske, Tavanna R.; Andrews, Catherine A.; Munroe, Robert J.; Hartford, Suzanne A.; Tye, Bik Kwoon; Schimenti, John C.

doi:10.1038/ng1936

Cited by 295 publications

(379 citation statements)

References 29 publications

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“…In two of our tumors with MCM4 mutations, this association could be defined mechanistically by genomic alteration of the family of MCM2-7 genes (43). Consistent with this hypothesis, prior studies have shown that Mcm protein deficiencies result in high rates of cancer in mouse models (44,45), catastrophic chromosomal rearrangements in human lymphoblasts in culture (46), and complex chromosomal alterations at discrete locations that are consistent with chromothripsis (43).…”

Section: Discussionsupporting

confidence: 60%

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Morrison

Liu

Woloszynska‐Read³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as "stitchers," to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication-licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer.next-generation sequencing | tumor heterogeneity | GRIN2A | replication

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Section: Discussionsupporting

confidence: 60%

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Morrison

Liu

Woloszynska‐Read³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…However, deregulation of the licensing system may also be a primary driver of oncogenesis, at least in some tumour types. For example, over-expression of Cdc6 or Cdt1 have been shown to be oncogenic, and deregulated Mcm7 expression has been linked to tumour formation, progression and malignant transformation in animal models [84][85][86][87][88][89][90]. Oncogenic mutations in genes upstream of the licensing machinery (eg RAS, CYCLINE and CYCLIND1 ) can also impact on tumourigenesis by causing deregulation of the licensing machinery.…”

Section: Dna Replication Licensing and Cancermentioning

confidence: 99%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

583

406

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Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

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“…More recently, two mouse models that recapitulate MCM loss-of-function situations have been reported. In the first one, a hypomorphic mutation in Mcm4 caused chromosome instability and increased the susceptibility to mammary adenocarcinomas (30). In the second one, a genetic manipulation of the 3Ј UTR in the MCM2 gene resulted in a mouse strain that expresses only a third of the normal concentration of Mcm2 protein.…”

Section: Dosage In Metazoanmentioning

confidence: 99%

Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication

Ibarra

Schwob

Méndez

2008

Proc. Natl. Acad. Sci. U.S.A.

452

465

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The six main minichromosome maintenance proteins (Mcm2-7), which presumably constitute the core of the replicative DNA helicase, are present in chromatin in large excess relative to the number of active replication forks. To evaluate the relevance of this apparent surplus of Mcm2-7 complexes in human cells, their levels were down-regulated by using RNA interference. Interestingly, cells continued to proliferate for several days after the acute (>90%) reduction of Mcm2-7 concentration. However, they became hypersensitive to DNA replication stress, accumulated DNA lesions, and eventually activated a checkpoint response that prevented mitotic division. When this checkpoint was abrogated by the addition of caffeine, cells quickly lost viability, and their karyotypes revealed striking chromosomal aberrations. Singlemolecule analyses revealed that cells with a reduced concentration of Mcm2-7 complexes display normal fork progression but have lost the potential to activate ''dormant'' origins that serve a backup function during DNA replication. Our data show that the chromatin-bound ''excess'' Mcm2-7 complexes play an important role in maintaining genomic integrity under conditions of replicative stress.DNA combing ͉ DNA replication ͉ origin licensing R apidly proliferating cells start to prepare for DNA replication several hours before the actual S-phase, with the assembly of prereplication complexes (pre-RCs) at origins in telophase and early G 1 . Pre-RC assembly, also referred to as ''origin licensing,'' consists in the recruitment of Mcm2-7 protein complexes by initiator proteins ORC, CDC6, and CDT1. ORC and CDC6 likely constitute a structural module with ATPase activity that opens and closes the ring-shaped MCM hexamer, facilitating its topological engagement with the DNA, whereas CDT1 cooperates in the loading reaction as a molecular chaperone (reviewed in refs. 1 and 2). Different lines of evidence indicate that Mcm2-7 constitute the core of the replicative DNA helicase in eukaryotic cells in association with CDC45 and the GINS complex (3, 4).The maximum number of origins available in the subsequent S-phase is predetermined at the licensing stage, because additional pre-RCs cannot be assembled later in the cell cycle because of the inhibitory activity of the S, G 2 and M-phase cyclin-dependent kinases. This regulation establishes a temporal alternation of origin licensing and firing that is important to prevent DNA overreplication. In yeast, blending the licensing and firing periods by deletion of the CDK inhibitor Sic1 or by overexpression of the G 1 cyclin Cln2, greatly increased genomic instability (5, 6). In human cells, premature expression of Cyclin E during mitosis and G 1 interfered with the association of MCM proteins with chromatin and at the same time promoted the firing of the limited number of licensed origins, effectively accelerating the G 1 -S transition (7). Nevertheless, cells continued to proliferate under these challenging conditions and accumulated karyotypic defects (8). These results are ...

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A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice

Cited by 295 publications

References 29 publications

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

The cell cycle and cancer

Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication

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