The contribution of dormant origins to genome stability: From cell biology to human genetics

Alver, Robert C.; Chadha, Gaganmeet Singh; Blow, J. Julian

doi:10.1016/j.dnarep.2014.03.012

Cited by 112 publications

(105 citation statements)

References 86 publications

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“…As stated above, loading of multiple DHs at many replication origins is a way to store large amounts of the inactive replicative helicase before DNA synthesis takes place (Alver et al 2014). Consistent with this notion, the DH is very stable even in the presence of high salt concentrations.…”

Section: Mcm2-7 Atp Hydrolysis Activities Of the Occm Dh And Cmgsupporting

confidence: 66%

From structure to mechanism—understanding initiation of DNA replication

et al. 2017

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DNA replication results in the doubling of the genome prior to cell division. This process requires the assembly of 50 or more protein factors into a replication fork. Here, we review recent structural and biochemical insights that start to explain how specific proteins recognize DNA replication origins, load the replicative helicase on DNA, unwind DNA, synthesize new DNA strands, and reassemble chromatin. We focus on the minichromosome maintenance (MCM2-7) proteins, which form the core of the eukaryotic replication fork, as this complex undergoes major structural rearrangements in order to engage with DNA, regulate its DNA-unwinding activity, and maintain genome stability.

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Section: Mcm2-7 Atp Hydrolysis Activities Of the Occm Dh And Cmgsupporting

confidence: 66%

From structure to mechanism—understanding initiation of DNA replication

et al. 2017

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“…14,43 Some of the effects of reduced Mcm loading might also be rescued by dormant origins, also contributing to the moderate phenotype. 44 However, despite the dormant origin hypothesis, it has been shown that reduced Mcm loading can lead to genomic instability especially when cells face additional replicative stress. 45,46 Interestingly, overexpression of Cdh1 causes the opposite phenotype with lengthening of G1, delayed entry into S phase and massive overreplication of the genome.…”

Section: Discussionmentioning

confidence: 99%

The role of APC/CCdh1 in replication stress and origin of genomic instability

et al. 2015

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It has been proposed that the APC/C(Cdh1) functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.

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“…Oncogene-induced replication stress is thought to induce firing of dormant origins, which facilitates completion of genome duplication (58). However, the observed increase in origin firing by GOF p53 was concomitant to S phase entry of cells and was dependent on TADI of GOF p53, needed to upregulate cyclin A expression ( Figure 5D).…”

Section: Methodsmentioning

confidence: 96%