Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome

Chabosseau, Pauline; Buhagiar-Labarchède, Géraldine; Onclercq-Delic, Rosine; Lambert, Sarah; Debatisse, Michèlle; Brison, Olivier; Amor‐Guéret, Mounira

doi:10.1038/ncomms1363

Cited by 68 publications

(93 citation statements)

References 33 publications

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“…Nucleotide homeostasis is closely related to human health and pathological conditions such as cancer development (Loffler et al 2005;Chabosseau et al 2011;Aird and Zhang 2015;Zauri et al 2015). Understanding how cells respond to and cope with related metabolic changes may also facilitate the development of therapeutic methods to treat these diseases.…”

Section: Discussionmentioning

confidence: 99%

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling inC. elegans

et al. 2016

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Animals alter their reproductive programs to accommodate changes in nutrient availability, yet the connections between known nutrient-sensing systems and reproductive programs are underexplored, and whether there is a mechanism that senses nucleotide levels to coordinate germline proliferation is unknown. We established a model system in which nucleotide metabolism is perturbed in both the nematode Caenorhabditis elegans (cytidine deaminases) and its food (Escherichia coli); when fed food with a low uridine/thymidine (U/T) level, germline proliferation is arrested. We provide evidence that this impact of U/T level on the germline is critically mediated by GLP-1/Notch and MPK-1/MAPK, known to regulate germline mitotic proliferation. This germline defect is suppressed by hyperactivation of glp-1 or disruption of genes downstream from glp-1 to promote meiosis but not by activation of the IIS or TORC1 pathways. Moreover, GLP-1 expression is post-transcriptionally modulated by U/T levels. Our results reveal a previously unknown nucleotide-sensing mechanism for controlling reproductivity.

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Section: Discussionmentioning

confidence: 99%

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling inC. elegans

et al. 2016

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“…Next, we attempted to rescue the fork speed in V-C8 and V79SM24 (HR − ) cells. In various mutant cell types, spontaneous RF slowing has been corrected by adding deoxynucleotide precursors (dNs) to the culture media (42)(43)(44)(45). Particularly in colorectal cancer cells, supplying dNs corrects slow replication and complex chromosome segregation errors, which were generated by the silencing of CIN (cancer chromosomal instability) suppressor genes, although centrosome number was not affected (46).…”

Section: Low Replication Stress Generates Anaphase Chromatin Bridges Andmentioning

confidence: 99%

Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells

Wilhelm

Magdalou

Barascu

et al. 2013

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

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Homologous recombination deficient (HR − ) mammalian cells spontaneously display reduced replication fork (RF) movement and mitotic extra centrosomes. We show here that these cells present a complex mitotic phenotype, including prolonged metaphase arrest, anaphase bridges, and multipolar segregations. We then asked whether the replication and the mitotic phenotypes are interdependent. First, we determined low doses of hydroxyurea that did not affect the cell cycle distribution or activate CHK1 phosphorylation but did slow the replication fork movement of wild-type cells to the same level than in HR − cells. Remarkably, these low hydroxyurea doses generated the same mitotic defects (and to the same extent) in wild-type cells as observed in unchallenged HR − cells. Reciprocally, supplying nucleotide precursors to HR − cells suppressed both their replication deceleration and mitotic extra centrosome phenotypes. Therefore, subtle replication stress that escapes to surveillance pathways and, thus, fails to prevent cells from entering mitosis alters metaphase progression and centrosome number, resulting in multipolar mitosis. Importantly, multipolar mitosis results in global unbalanced chromosome segregation involving the whole genome, even fully replicated chromosomes. These data highlight the crosstalk between chromosome replication and segregation, and the importance of HR at the interface of these two processes for protection against general genome instability.

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“…CDA deficiency leads to an intracellular accumulation of dCTP (Chabosseau et al, 2011;Gemble et al, 2015). The addition of dC to the culture medium of CDA-proficient cells reproduces the increase in dCTP levels observed in CDA-deficient cells, mimicking CDA deficiency (Chabosseau et al, 2011;Gemble et al, 2015).…”

Section: Resultsmentioning

confidence: 75%

“…The addition of dC to the culture medium of CDA-proficient cells reproduces the increase in dCTP levels observed in CDA-deficient cells, mimicking CDA deficiency (Chabosseau et al, 2011;Gemble et al, 2015). We treated CDA-proficient and CDA-deficient cells with dC before CPT treatment.…”

Section: Resultsmentioning

confidence: 91%

“…Replication stress is defined as any phenomenon affecting completion of the DNA replication program, including alterations to the initiation and elongation steps of DNA replication, conflicts between DNA replication and metabolic pathways, such as transcription and mRNA processing, nucleotide pool disequilibrium, and the overexpression or activation of oncogenes (Hills and Diffley, 2014;Lecona and Fernandez-Capetillo, 2014;Magdalou et al, 2014;Mazouzi et al, 2014). Such stress can jeopardize the completion of DNA replication and chromosome segregation, as illustrated by our previous studies showing that pyrimidine pool disequilibrium resulting from cytidine deaminase (CDA) deficiency is a source of replication stress and subsequent segregation defects (Chabosseau et al, 2011;Gemble et al, 2015). CDA is an enzyme of the pyrimidine salvage pathway that catalyzes the hydrolytic deamination of cytidine and deoxycytidine into uridine and deoxyuridine, respectively (Nygaard, 1986).…”

Section: Introductionmentioning

confidence: 99%

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A balanced pyrimidine pool is required for optimal Chk1 activation to prevent ultrafine anaphase bridge formation

Gemble

Buhagiar-Labarchède

Onclercq-Delic

et al. 2016

Journal of Cell Science

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Cytidine deaminase (CDA) deficiency induces an excess of cellular dCTP, which reduces basal PARP-1 activity, thereby compromising complete DNA replication, leading to ultrafine anaphase bridge (UFB) formation. CDA dysfunction has pathological implications, notably in cancer and in Bloom syndrome. It remains unknown how reduced levels of PARP-1 activity and pyrimidine pool imbalance lead to the accumulation of unreplicated DNA during mitosis. We report that a decrease in PARP-1 activity in CDA-deficient cells impairs DNAdamage-induced Chk1 activation, and, thus, the downstream checkpoints. Chemical inhibition of the ATR-Chk1 pathway leads to UFB accumulation, and we found that this pathway was compromised in CDA-deficient cells. Our data demonstrate that ATR-Chk1 acts downstream from PARP-1, preventing the accumulation of unreplicated DNA in mitosis, and, thus, UFB formation. Finally, delaying entry into mitosis is sufficient to prevent UFB formation in both CDA-deficient and CDA-proficient cells, suggesting that both physiological and pathological UFBs are derived from unreplicated DNA. Our findings demonstrate an unsuspected requirement for a balanced nucleotide pool for optimal Chk1 activation both in unchallenged cells and in response to genotoxic stress.

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Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome

Cited by 68 publications

References 33 publications

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling inC. elegans

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling inC. elegans

Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells

A balanced pyrimidine pool is required for optimal Chk1 activation to prevent ultrafine anaphase bridge formation

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