Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs (Review)

Chen, Zhangming; Hu, Jie; Shi, Ying; Xu, Aman

doi:10.3892/ol.2021.12712

Cited by 5 publications

(13 citation statements)

References 83 publications

(116 reference statements)

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“…Promotor methylation and miRNAs have been described to be involved in SAMHD1 regulation [de Silva et al, 2013; Kohnken et al, 2017; Chen et al, 2021]. Tumour and normal sample SAMHD1 expression and promoter methylation beta values were available for 18 cancer types in TCGA.…”

Section: Resultsmentioning

confidence: 99%

“…Taken together, SAMHD1 levels are determined by complex regulation mechanisms that include promotor methylation and miRNAs, together with post-translational modifications such as phosphorylation and acetylation that have also been described [Coggins et al, 2020; Chen et al, 2021].…”

Section: Resultsmentioning

confidence: 99%

“…In the meantime, SAMHD1 has been shown to exert a range of additional functions [Mauney & Hollis, 2018; Coggins et al, 2020; Chen et al, 2021]. As a deoxynucleoside triphosphate hydrolase (dNTPase), that cleaves deoxynucleoside triphosphates (dNTPs) into deoxynucleosides and triphosphate, SAMHD1 plays, together with enzymes that catalyse dNTP biosynthesis, an important role in the maintenance of balanced cellular dNTP pools [Mauney & Hollis, 2018; Coggins et al, 2020; Chen et al, 2021]. Since imbalances in cellular dNTP pools affect cell cycle regulation and DNA stability, SAMHD1 is also involved in the regulation of these processes [Chen et al, 2021].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to controlling cellular dNTP levels, SAMHD1 has been shown to maintain genome integrity by a range of further mechanisms, including maintenance of telomere integrity, inhibition of LINE-1 retrotransposons, facilitation of homologous recombination-mediated double-strand break repair and DNA end joining, and prevention of R-loop formation at transcription-replication conflict regions [Herold et al, 2017a; Akimova et al, 2021; Chen et al, 2021; Park et al, 2021]. Additionally, low SAMHD1 levels have been detected in chronic lymphocytic leukaemia (CLL), lung cancer, cutaneous T-cell lymphoma, AML, colorectal cancer, and Hodgkin lymphoma.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, low SAMHD1 levels have been detected in chronic lymphocytic leukaemia (CLL), lung cancer, cutaneous T-cell lymphoma, AML, colorectal cancer, and Hodgkin lymphoma. Moreover, loss-of-function SAMHD1 mutations have been described in cancer types including CLL and colorectal cancer [Herold et al, 2017a; Mauney & Hollis, 2018; Coggins et al, 2020; Chen et al, 2021]. Due to these observations, SAMHD1 is being considered as a tumour suppressor protein.…”

Section: Introductionmentioning

confidence: 99%

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Multifaceted roles of SAMHD1 in cancer

McLaughlin

Činátl

Wass

et al. 2021

Preprint

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SAMHD1 is discussed as a tumour suppressor protein, but its potential role in cancer has only been investigated in very few cancer types. Here, we performed a systematic analysis of the TCGA (adult cancer) and TARGET (paediatric cancer) databases, the results of which did not suggest that SAMHD1 should be regarded as a bona fide tumour suppressor. SAMHD1 mutations that interfere with SAMHD1 function were not associated with poor outcome, which would be expected for a tumour suppressor. High SAMHD1 tumour levels were associated with increased survival in some cancer entities and reduced survival in others. Moreover, the data suggested differences in the role of SAMHD1 between males and females and between different races. Often, there was no significant relationship between SAMHD1 levels and cancer outcome. Taken together, our results indicate that SAMHD1 may exert pro- or anti-tumourigenic effects and that SAMHD1 is involved in the oncogenic process in a minority of cancer cases. These findings seem to be in disaccord with a perception and narrative forming in the field suggesting that SAMHD1 is a tumour suppressor. A systematic literature review confirmed that most of the available scientific articles focus on a potential role of SAMHD1 as a tumour suppressor. The reasons for this remain unclear but may include confirmation bias and publication bias. Our findings emphasise that hypotheses, perceptions, and assumptions need to be continuously challenged by using all available data and evidence.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multifaceted roles of SAMHD1 in cancer

McLaughlin

Činátl

Wass

et al. 2021

Preprint

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Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Stankovic

Shekari

Huang

et al. 2022

Preprint

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Human genetic studies have provided substantial insight into the biological mechanisms governing ovarian ageing, yet previous approaches have been largely restricted to assessing common genetic variation. Here we report analyses of rare (MAF<0.1%) protein-coding variants in the exomes of 106,973 women from the UK Biobank study, implicating novel genes with effect sizes up to ~5 times larger than previously discovered in analyses of common variants. These include protein truncating variants in ZNF518A, which shorten reproductive lifespan by promoting both earlier age at natural menopause (ANM, 5.61 years [4.04-7.18], P=2*10-12) and later puberty timing in girls (age at menarche, 0.56 years [0.15-0.97], P=9.2*10-3). By integrating ChIP-Seq data, we demonstrate that common variants associated with ANM and menarche are enriched in the binding sites of ZNF518A. We also identify further links between ovarian ageing and cancer susceptibility, highlighting damaging germline variants in SAMHD1 that delay ANM and increase all-cause cancer risk in both males (OR=2.1 [1.7-2.6], P=4.7*10-13) and females (OR=1.61 [1.31-1.96], P=4*10-6). Finally, we demonstrate that genetic susceptibility to earlier ovarian ageing in women increases de novo mutation rate in their offspring. This provides direct evidence that female mutation rate is heritable and highlights an example of a mechanism for the maternal genome influencing child health.

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Genome-wide screens connect HD82 loss-of-function to purine analog resistance in African trypanosomes

Trenaman,

Tinti,

Atrih

et al. 2024

mSphere

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Nucleoside analogs have been used extensively as anti-infective agents, particularly against viral infections, and have long been considered promising anti-parasitic agents. These pro-drugs are metabolized by host-cell, viral, or parasite enzymes prior to incorporation into DNA, thereby inhibiting DNA replication. Here, we report genes that sensitize African trypanosomes to nucleoside analogs, including the guanosine analog, ganciclovir. We applied ganciclovir selective pressure to a trypanosome genome-wide knockdown library, which yielded nucleoside mono- and diphosphate kinases as hits, validating the approach. The two most dominant hits to emerge, however, were Tb927.6.2800 and Tb927.6.2900, which both encode nuclear proteins; the latter of which is HD82, a SAMHD1-related protein and a putative dNTP triphosphohydrolase. We independently confirmed that HD82, which is conserved among the trypanosomatids, can sensitize Trypanosoma brucei to ganciclovir. Since ganciclovir activity depends upon phosphorylation by ectopically expressed viral thymidine kinase, we also tested the adenosine analog, ara-A, that may be fully phosphorylated by native T. brucei kinase(s). Both Tb927.6.2800 and HD82 knockdowns were resistant to this analog. Tb927.6.2800 knockdown increased sensitivity to hydroxyurea, while dNTP analysis indicated that HD82 is indeed a triphosphohydrolase with dATP as the preferred substrate. Our results provide insights into nucleoside/nucleotide metabolism and nucleoside analog metabolism and resistance in trypanosomatids. We suggest that the product of 6.2800 sensitizes cells to purine analogs through DNA repair, while HD82 does so by reducing the native purine pool. IMPORTANCE There is substantial interest in developing nucleoside analogs as anti-parasitic agents. We used genome-scale genetic screening and discovered two proteins linked to purine analog resistance in African trypanosomes. Our screens also identified two nucleoside kinases required for pro-drug activation, further validating the approach. The top novel hit, HD82, is related to SAMHD1, a mammalian nuclear viral restriction factor. We validated HD82 and localized the protein to the trypanosome nucleus. HD82 appears to sensitize trypanosomes to nucleoside analogs by reducing native pools of nucleotides, providing insights into both nucleoside/nucleotide metabolism and nucleoside analog resistance in trypanosomatids.

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Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs (Review)

Cited by 5 publications

References 83 publications

Multifaceted roles of SAMHD1 in cancer

Multifaceted roles of SAMHD1 in cancer

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Genome-wide screens connect HD82 loss-of-function to purine analog resistance in African trypanosomes

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