A defective dNTP pool hinders DNA replication in cell cycle-reactivated terminally differentiated muscle cells

Pajalunga, Deborah; Franzolin, Elisa; Stevanoni, Martina; Zribi, Sara; Passaro, Nunzia; Gurtner, Aymone; Donsante, Samantha; Loffredo, Daniela; Losanno, Lidia; Bianchi, Vera; Russo, Antonella; Rampazzo, Chiara; Crescenzi, Marco

doi:10.1038/cdd.2017.4

Cited by 17 publications

(11 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, this deletion caused a 2.5-fold increase in dNTP levels, indicating that replication fork velocity is sensitive to changes in dNTP levels. Studies in human cells have shown similar results [85][86][87], particularly in the context of early cancer stages [88]. In a model of the aberrant activation of the Rb-E2F pathway by cellular oncogenes, the overexpression of cyclin E in human fibroblasts resulted in a dramatic reduction in the dNTP pool, which was associated with a decrease in fork speed.…”

Section: Variations In Dna Componentsmentioning

confidence: 73%

Replication Stress, Genomic Instability, and Replication Timing: A Complex Relationship

Briu

Maric

Cadoret

2021

IJMS

View full text Add to dashboard Cite

The replication-timing program constitutes a key element of the organization and coordination of numerous nuclear processes in eukaryotes. This program is established at a crucial moment in the cell cycle and occurs simultaneously with the organization of the genome, thus indicating the vital significance of this process. With recent technological achievements of high-throughput approaches, a very strong link has been confirmed between replication timing, transcriptional activity, the epigenetic and mutational landscape, and the 3D organization of the genome. There is also a clear relationship between replication stress, replication timing, and genomic instability, but the extent to which they are mutually linked to each other is unclear. Recent evidence has shown that replication timing is affected in cancer cells, although the cause and consequence of this effect remain unknown. However, in-depth studies remain to be performed to characterize the molecular mechanisms of replication-timing regulation and clearly identify different cis- and trans-acting factors. The results of these studies will potentially facilitate the discovery of new therapeutic pathways, particularly for personalized medicine, or new biomarkers. This review focuses on the complex relationship between replication timing, replication stress, and genomic instability.

show abstract

Section: Variations In Dna Componentsmentioning

confidence: 73%

Replication Stress, Genomic Instability, and Replication Timing: A Complex Relationship

Briu

Maric

Cadoret

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…In this study, the ndings revealed that supplementation with exogenous nucleotides could inhibit the caspase activation induced by silencing SIRT5. Moreover, an abnormal pool of dNTP was shown to halt DNA replication during the S-phase 46 . Similarly, the present study revealed that addition of four nucleotides could reverse the cell cycle arrest induced by shortage of dNTPs, corroborating with previous studies which showed that the levels of dNTPs regulated the cell cycle by activating the DNA checkpoint 47,48 .…”

Section: Discussionmentioning

confidence: 99%

Silencing Sirtuin5 induces DNA damage by suppressing the pentose phosphate pathway in a demalonylation-dependent manner: A possible target for anticancer therapy in CRC

Wang

Chen²,

Wang³

et al. 2021

Preprint

View full text Add to dashboard Cite

A previous study by our research group showed that sirtuin5 (SIRT5), a member of the class III NAD＋-dependent deacetylase family, is highly expressed in colorectal cancer (CRC). The present study showed that deletion of SIRT5 induced cell cycle arrest and apoptosis as a result of continuous and irreparable DNA damage in CRC cells, a consequence of the impaired production of ribose-5-phosphate (R5P) which is essential for nucleotide synthesis. Consistently, the cell cycle arrest and apoptosis induced by SIRT5 silencing could be reversed by supplementation with four nucleotides. Moreover, metabolic profiling revealed that silencing of SIRT5 could inhibit the non-oxidative pentose phosphate pathway (PPP), which produces R5P, required for base ribosylation. Notably, SIRT5 activates transketolase (TKT), the key enzyme in the cellular non-oxidative PPP, by mediating its lysine demalonylation through the interaction between SIRT5 and TKT. Furthermore, the results demonstrated that TKT is essential for the SIRT5-induced malignant phenotypes of CRC, both in vivo and in vitro. These results therefore revealed that the increased lysine malonylation levels of TKT caused by silencing SIRT5 suppresses non-oxidative pentose phosphate metabolism, leading to a low-nucleotide pool. This in turn induces DNA damage in tumor cells and inhibits proliferation, suggesting that SIRT5 may serve as a potential anticancer target.

show abstract

“…The fast embryonic cell cycles may have very different requirement for dNTP levels than cultured cells in vitro, for example [82]. It has been proposed that defective dNTP pool halts DNA replication during S-phase in cultured mammalian cells [83,84]. The defective pool may include shortages of dNTP precursors, enzymes or dNTPs themselves, and always leads to replication stress and checkpoint activation [85,86].…”

Section: Mechanisms Of Cell Cycle Control By Dntpmentioning

confidence: 99%

The role of dNTP metabolites in control of the embryonic cell cycle

Liu

Großhans

2019

Cell Cycle

View full text Add to dashboard Cite

Deoxyribonucleotide metabolites (dNTPs) are the substrates for DNA synthesis. It has been proposed that their availability influences the progression of the cell cycle during development and pathological situations such as tumor growth. The mechanism has remained unclear for the link between cell cycle and dNTP levels beyond their role as substrates. Here, we review recent studies concerned with the dynamics of dNTP levels in early embryos and the role of DNA replication checkpoint as a sensor of dNTP levels.

show abstract

A defective dNTP pool hinders DNA replication in cell cycle-reactivated terminally differentiated muscle cells

Cited by 17 publications

References 40 publications

Replication Stress, Genomic Instability, and Replication Timing: A Complex Relationship

Replication Stress, Genomic Instability, and Replication Timing: A Complex Relationship

Silencing Sirtuin5 induces DNA damage by suppressing the pentose phosphate pathway in a demalonylation-dependent manner: A possible target for anticancer therapy in CRC

The role of dNTP metabolites in control of the embryonic cell cycle

Contact Info

Product

Resources

About