Increased replication origin firing links replication stress to whole chromosomal instability in human cancer

Böhly, Nicolas; Schmidt, Ann-Kathrin; Zhang, Xiaoxiao; Slusarenko, Benjamin O.; Hennecke, Magdalena; Kschischo, Maik; Bastians, Holger

doi:10.1016/j.celrep.2022.111836

Cited by 23 publications

(11 citation statements)

References 86 publications

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“…In metazoa and yeast, CMG formation involves the factors Treslin/Sld3, MTBP/Sld7, RecQL4/DONSON/Sld2, TopBP1/Dpb11 and the Mcm2-7 helicase itself. Apart from coupling origin firing to the S phase via S-CDK and DDK, these signal integrators are targeted by the DNA damage checkpoint and other regulatory pathways to mediate DNA damage-dependent origin firing control, execution of the temporal replication program and fine-tuning of origin firing 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 . Such regulation helps avoid replication stress that is key to structural and numerical chromosomal instability in cancer cells 68 .…”

Section: Discussionmentioning

confidence: 99%

TopBP1 utilises a bipartite GINS binding mode to support genome replication

Day

Tetik

Parlak

et al. 2023

Preprint

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How the replicative Mcm2-7 helicase is activated during replication origin firing remains largely unknown. Our biochemical and structural studies reported here, demonstrate that the helicase activator GINS interacts with TopBP1 through two separate binding surfaces, the first involving a stretch of highly conserved amino acids in the TopBP1-GINI region, the second a surface located on TopBP1-BRCT4. The two surfaces bind to opposite ends of the A domain of the GINS subunit Psf1, and their cooperation is required for a biochemically stable TopBP1-GINS interaction. The GINI and BRCT4 domains also cooperate during replication origin firing, as revealed by immuno-replacement experiments in Xenopus egg extracts using different sets of mutations in either interface. Furthermore, the TopBP1-GINS interaction is incompatible with simultaneous binding of DNA polymerase epsilon to GINS when bound to Mcm2-7-Cdc45. Our TopBP1-GINS model predicts the coordination of three molecular processes, DNA polymerase epsilon arrival, TopBP1 ejection and GINS integration into Mcm2-7-Cdc45.

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Section: Discussionmentioning

confidence: 99%

TopBP1 utilises a bipartite GINS binding mode to support genome replication

Day

Tetik

Parlak

et al. 2023

Preprint

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“…Impaired DNA synthesis during S-phase is termed replication stress, and can be due to several disparate factors such as DNA adducts (26, 27), nucleotide depletion (9, 28), or inhibition of the DNA polymerase (29, 30). Inhibition of the DNA polymerase and DNA lesions can lead to uncoupling of the Cdc45, Mcm2– 7, GINS (CMG) helicase from DNA polymerase (31, 32).…”

Section: Resultsmentioning

confidence: 99%

Transient Zn²⁺deficiency induces replication stress and compromises daughter cell proliferation

Holtzen,

Navid,

Kainov

et al. 2023

Preprint

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Cells must replicate their genome quickly and accurately, and they require metabolites and cofactors to do so. Ionic zinc (Zn2+) is an essential micronutrient that is required for hundreds of cellular processes, including DNA synthesis and adequate proliferation. Deficiency in this micronutrient impairs DNA synthesis and inhibits proliferation, but the mechanism is unknown. Using fluorescent reporters to track single cells via long-term live-cell imaging, we find that Zn2+is required at the G1/S transition and during S-phase for timely completion of S-phase. A short pulse of Zn2+deficiency impairs DNA synthesis and increases markers of replication stress. These markers of replication stress are reversed upon resupply of Zn2+. Finally, we find that if Zn2+is removed during the mother cell’s S-phase, daughter cells enter a transient quiescent state, maintained by sustained expression of p21, which disappears upon reentry into the cell cycle. In summary, short pulses of mild Zn2+deficiency in S-phase specifically induce replication stress, which causes downstream proliferation impairments in daughter cells.SignificanceZinc is an essential micronutrient required for cells to grow and proliferate. However, the mechanism of how zinc influences proliferation is unknown. We show that short exposure to mild zinc deficiency in S-phase impairs DNA synthesis and induces replication stress, leading to pauses in daughter cell proliferation. However, pulses of low zinc during other phases of the cell cycle don’t affect mother cell cycle progression or daughter cell proliferation. These results indicate that while zinc is important for many proteins, during the cell cycle short pulses of mild zinc deficiency have the biggest impact on a cell’s ability to synthesize DNA, suggesting that DNA polymerase complex acts as a gate keeper, sensing zinc status in the cell.

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“…A similar effect occurs when essential cell cycle genes for DNA replication, such as GINS1 or CDC45, are overexpressed in chromosomally stable HCT116 cells. Elevated levels of GINS1 or CDC45 cause increased replication origin firing, which interestingly leads to altered microtubule dynamics during mitosis and subsequent chromosome missegregation and eventually WGD ( Böhly et al, 2022 ). Similar data have been described by others showing that the induction of replication stress, by a variety of means, results in whole chromosome missegregation ( Greil et al, 2015 ; Wilhelm et al, 2019 ).…”

Section: Genetic Determinants Modulating the Wgd Oncogenic-suppressor...mentioning

confidence: 99%

Whole-Genome Doubling as a source of cancer: how, when, where, and why?

Sanz-Gómez

González-Alvarez

Rivas

et al. 2023

Front. Cell Dev. Biol.

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Chromosome instability is a well-known hallmark of cancer, leading to increased genetic plasticity of tumoral cells, which favors cancer aggressiveness, and poor prognosis. One of the main sources of chromosomal instability are events that lead to a Whole-Genome Duplication (WGD) and the subsequently generated cell polyploidy. In recent years, several studies showed that WGD occurs at the early stages of cell transformation, which allows cells to later become aneuploid, thus leading to cancer progression. On the other hand, other studies convey that polyploidy plays a tumor suppressor role, by inducing cell cycle arrest, cell senescence, apoptosis, and even prompting cell differentiation, depending on the tissue cell type. There is still a gap in understanding how cells that underwent WGD can overcome the deleterious effect on cell fitness and evolve to become tumoral. Some laboratories in the chromosomal instability field recently explored this paradox, finding biomarkers that modulate polyploid cells to become oncogenic. This review brings a historical view of how WGD and polyploidy impact cell fitness and cancer progression, and bring together the last studies that describe the genes helping cells to adapt to polyploidy.

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Increased replication origin firing links replication stress to whole chromosomal instability in human cancer

Cited by 23 publications

References 86 publications

TopBP1 utilises a bipartite GINS binding mode to support genome replication

TopBP1 utilises a bipartite GINS binding mode to support genome replication

Transient Zn²⁺deficiency induces replication stress and compromises daughter cell proliferation

Whole-Genome Doubling as a source of cancer: how, when, where, and why?

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Increased replication origin firing links replication stress to whole chromosomal instability in human cancer

Cited by 23 publications

References 86 publications

TopBP1 utilises a bipartite GINS binding mode to support genome replication

TopBP1 utilises a bipartite GINS binding mode to support genome replication

Transient Zn2+deficiency induces replication stress and compromises daughter cell proliferation

Whole-Genome Doubling as a source of cancer: how, when, where, and why?

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Transient Zn²⁺deficiency induces replication stress and compromises daughter cell proliferation