Defective modulation of LINE-1 retrotransposition by cancer-associated SAMHD1 mutants

Gao, Wenying; Li, Guangquan; Bian, Xuefeng; Rui, Yajuan; Zhai, Chenyang; Liu, Panpan; Su, Jiaming; Wang, Hong; Zhu, Chunfeng; Du, Yanjia; Zheng, Wenwen; Zheng, Baisong; Zhang, Wenyan; Zhang, Hui; Zhao, Ke; Yang, Yongjun; Yu, Xiaofang

doi:10.1016/j.bbrc.2019.08.155

Cited by 6 publications

(6 citation statements)

References 29 publications

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“…In addition, a previous study has reported more mutants of SAMHD1 protein in various types of cancer (Fig. 2) (20). Furthermore, SAMHD1 single-nucleotide polymorphisms (SNPs) at seven codon positions negatively regulate the retrotransposition of LINE-1 compared with its wild-type equivalent (48).…”

Section: Samhd1 Inhibits the Development Of Numerous Types Of Tumormentioning

confidence: 98%

“…Methylation at the promoter of SAMHD1 has been demonstrated to decrease its mRNA and protein expression (14), and the functions of SAMHD1 are affected by acetylation (16) and phosphorylation (17). In particular, SAMHD1 is involved in DNA damage repair (DDR) (18), long interspersed element type 1 (LINE-1) suppression (19,20) and chemosensitivity to anticancer drugs (21,22). In addition, genetic mutations of SAMHD1 contribute to amino acid changes, which in part impair its functions (11,15).…”

Section: Dual Roles Of Samhd1 In Tumor Development and Chemoresistancmentioning

confidence: 99%

“…The enzymatically active HD domain of SAMHD1, SAM domain, is therefore crucial for the inhibition of LINE-1 retrotransposon. The dNTPase-inactive SAMHD1 mutants H206A/D207A and K288T can also inhibit the reverse transcription of LINE-1 in colon cancer (20,48). Removing the nuclear localization sequence of SAMHD1 or its K11A mutants could subsequently induce its redistribution in the cytoplasm, leading to ORF2p deletion and LINE-1 suppression, but with no effect on dNTPase activity (49,50).…”

Section: Samhd1 Inhibits the Development Of Numerous Types Of Tumormentioning

confidence: 99%

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

Chen

Shi

et al. 2021

Oncol Lett

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Human sterile alpha motif and HD-domaincontaining protein 1 (SAMHD1) has been identified as a GTP or dGTP-dependent deoxynucleotide triphosphohydrolase (dNTPase) and acts as an antiviral factor against certain retroviruses and DNA viruses. Genetic mutation in SAMHD1 causes the inflammatory Aicardi-Goutières Syndrome and abnormal intracellular deoxyribonucleoside triphosphates (dNTPs) pool. At present, the role of SAMHD1 in numerous types of cancer, such as chronic lymphocytic leukemia, lung cancer and colorectal cancer, is highly studied. Furthermore, it has been found that methylation, acetylation and phosphorylation are involved in the regulation of SAMHD1 expression, and that genetic mutations can cause changes in its activities, including dNTPase activity, long interspersed element type 1 (LINE-1) suppression and DNA damage repair, which could lead to uncontrolled cell cycle progression and cancer development. In addition, SAMHD1 has been reported to have a negative regulatory role in the chemosensitivity to anticancer drugs through its dNTPase activity. The present review aimed to summarize the regulation of SAMHD1 expression in cancer and its function in tumor growth and chemotherapy sensitivity, and discussed controversial points and future directions. Contents 1. Introduction 2. Role of methylation, acetylation and phosphorylation in the regulation of SAMHD1 expression in cancer 3. SAMHD1 inhibits the development of numerous types of tumor 4. SAMHD1 is a negative regulator of nucleotide analogs in vitro and in vivo. 5. Future directions and conclusion

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Section: Samhd1 Inhibits the Development Of Numerous Types Of Tumormentioning

confidence: 98%

Section: Dual Roles Of Samhd1 In Tumor Development and Chemoresistancmentioning

confidence: 99%

Section: Samhd1 Inhibits the Development Of Numerous Types Of Tumormentioning

confidence: 99%

See 1 more Smart Citation

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

Chen

Shi

et al. 2021

Oncol Lett

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“…Cancer-associated mutations, which are scattered throughout the SAMHD1 gene, have been found to modulate in vivo SAMHD1 activity and expression levels [56,228]. Several SAMHD1 cancer-related mutations were shown to have a loss in negatively modulating LINE-1 [233]. This is interesting because SAMHD1 also harbors the ability to bind DNA and RNA through its HD domain, a function in which the SAM domain is dispensable [47,129].…”

Section: Samhd1 Is Downregulated In Various Cancers and Has Differentmentioning

confidence: 99%

SAMHD1 Functions and Human Diseases

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Mahboubi

Schinazi

et al. 2020

Viruses

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Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been extensively investigated, a negative regulatory mechanism of dNTP pools was recently found to involve sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, dNTP triphosphohydrolase activity of SAMHD1 degrades dNTPs into their 2′-deoxynucleoside (dN) and triphosphate subparts, steadily depleting intercellular dNTP pools. The differential expression levels and activation states of SAMHD1 in various cell types contributes to unique dNTP pools that either aid (i.e., dividing T cells) or restrict (i.e., nondividing macrophages) viral replication that consumes cellular dNTPs. Genetic mutations in SAMHD1 induce a rare inflammatory encephalopathy called Aicardi–Goutières syndrome (AGS), which phenotypically resembles viral infection. Recent publications have identified diverse roles for SAMHD1 in double-stranded break repair, genome stability, and the replication stress response through interferon signaling. Finally, a series of SAMHD1 mutations were also reported in various cancer cell types while why SAMHD1 is mutated in these cancer cells remains to investigated. Here, we reviewed a series of studies that have begun illuminating the highly diverse roles of SAMHD1 in virology, immunology, and cancer biology.

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“…It has also been found that the mutant of SAMHD1 has a defect in LINE-1 inhibition. At the same time, the ability of SAMHD1 to inhibit ORF2p-mediated LINE-1 RNP reverse transcription has been shown to be associated with SAMHD1-mediated LINE-1 inhibition (86). Furthermore, SAMHD1 attenuates IFN-and T-cell-mediated responses by suppressing the induction of virus-specific cytotoxic T-cells in vivo (87).…”

Section: Role Of Samhd1 In Immune Disorders and Viral Infectionsmentioning

confidence: 99%

Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review)

et al. 2020

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Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), the only deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, plays a crucial role in regulating the dynamic balance and ratio of cellular dNTP pools. Furthermore, SAMHD1 has been reported to be involved in the pathological process of several diseases. Homozygous SAMHD1 mutations have been identified in immune system disorders, such as autoimmune disease Aicardi-Goutières syndrome (AGS), whose primary pathogenesis is associated with the abnormal accumulation and disproportion of dNTPs. SAMHD1 is also considered to be an intrinsic virus-restriction factor by suppressing the viral infection process, including reverse transcription, replication, packaging and transmission. In addition, SAMHD1 has been shown to promote genome integrity during homologous recombination following DNA damage, thus being considered a promising candidate for oncotherapy applications. The present review summarizes the molecular mechanisms of SAMHD1 regarding the regulation of dNTP homeostasis and DNA damage response. Additionally, its potential effects on tumorigenesis and oncotherapy are reported.

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Defective modulation of LINE-1 retrotransposition by cancer-associated SAMHD1 mutants

Cited by 6 publications

References 29 publications

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

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

SAMHD1 Functions and Human Diseases

Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review)

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