Role of the NUDT Enzymes in Breast Cancer

Wright, Roni H. G.; Beato, Miguel

doi:10.3390/ijms22052267

Cited by 25 publications

(14 citation statements)

References 70 publications

(52 reference statements)

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“…4b). This correlates with the previously described role of other members of the NUDIX protein superfamily in breast cancer 32 . In addition, breast cancer patients 33 with NUDT22 alterations have a worse prognosis in overall survival which was not recapitulated in alterations in UMPS or DHODH (Fig.…”

Section: Nudt22 De Ciency Reduces Cancer Growthsupporting

confidence: 91%

NUDT22 promotes cancer growth through pyrimidine salvage and the TCA cycle

Walter

Mayr

Hanna

et al. 2022

Preprint

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The NUDIX hydrolase NUDT22 converts UDP-glucose into glucose-1-phosphate and the pyrimidine nucleotide uridine monophosphate1. Glucose-1-phosphate is an important metabolite for energy and biomass production through glycolysis and the subsequent tricarboxylic acid (TCA) cycle and nucleotides required for DNA replication are produced through energetically expensive de novo or energy-efficient salvage pathways2. Here, we describe p53-regulated pyrimidine and glucose-1-phosphate salvage through NUDT22-dependent hydrolysis of UDP-glucose to maintain cancer cell growth and to prevent replication stress. We identified elevated NUDT22 expression in cancer tissues and reduced TCA intermediates and oncometabolites, growth retardation, S-phase delay, and slower DNA replication forks in NUDT22-deficient cancer cells. NUDT22 transcription is induced under starvation, oncogenic stress, and DNA damage directly through p53. Uridine supplementation rescues replication fork progression and alleviates replication stress. Conversely, NUDT22 deficiency sensitizes cells to de novo pyrimidine synthesis inhibition in vitro and reduces cancer growth in vivo. In conclusion, NUDT22 maintains pyrimidine supply and provides a substrate for the TCA cycle in cancer cells. Depletion of NUDT22 leads to genome instability and a reduction in TCA cycle metabolites, including oncometabolites such as 2-hydroxyglutarate and succinate. Targeting NUDT22 therefore has high potential for therapeutic applications in cancer therapy, simultaneously interfering with two essential survival pathways.

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Section: Nudt22 De Ciency Reduces Cancer Growthsupporting

confidence: 91%

NUDT22 promotes cancer growth through pyrimidine salvage and the TCA cycle

Walter

Mayr

Hanna

et al. 2022

Preprint

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“…Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) transforms the last ADPR group, into phosphoribose bound to the proteins leaving 5′AMP. Similarly, nucleoside diphosphates linked to some moiety X (NUDX/NUDT) hydrolases cleave ADP-ribose to produce 5′ AMP and ribose-5-phosphate (R5P) [ 16 , 52 , 53 ]. Various NUDIX/NUDT enzymes are overexpressed in cancers.…”

Section: Erasersmentioning

confidence: 99%

“…MacroD1 is also named leukemia-related protein 16 (LRP16). An aberrant MacroD1 expression has been associated with leukemia and breast, colorectal, gastric, lung, and liver cancers [ 53 , 54 ]. When overexpressed, MacroD2 is associated with estrogen-independent growth and tamoxifen resistance in breast cancer [ 50 , 56 ].…”

Section: Erasersmentioning

confidence: 99%

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri

Misawa

Masutani

2021

IJMS

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Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

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“…Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) transforms the last ADPR group,into phosphoribose bound to the proteins leaving 5'AMP. Similarly, nucleoside diphosphates linked to some moiety X (NUDX/NUDT) hydrolases cleave ADP-ribose to produce 5' AMP and ribose-5-phosphate (R5P) [52,53,16]. Various NUDIX/NUDT enzymes are overexpressed in cancers, in particular NUDT2 and NUDT5 are linked to aggressive adenocarcinomas and homologous recombination (HR)positive breast cancers, respectively [52] linking them to ADPR catabolism and NAD + salvage pathway [54,55].…”

Section: Erasersmentioning

confidence: 99%

“…MacroD1 is also named leukemia-related protein 16 (LRP16). Aberrant MacroD1 expression has been associated with leukemia, breast, colorectal, gastric, lung and liver cancers [53,54]. MacroD2 when overexpressed is associated with estrogen independent growth and tamoxifen resistance in breast cancer [50,56].…”

Section: Erasersmentioning

confidence: 99%

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri¹,

Misawa²,

Masutani³

2021

Preprint

View full text Add to dashboard Cite

Among post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, assigning to this PTM a large set of functions, including DNA repair, transcription and cell signaling. This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing MAR/PAR cycling in cancers. Of note, there is potential for application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

show abstract

Role of the NUDT Enzymes in Breast Cancer

Cited by 25 publications

References 70 publications

NUDT22 promotes cancer growth through pyrimidine salvage and the TCA cycle

NUDT22 promotes cancer growth through pyrimidine salvage and the TCA cycle

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

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