Structural and functional characterization explains loss of dNTPase activity of the cancer-specific R366C/H mutant SAMHD1 proteins

Bowen, Nicole E.; Temple, Joshua; Shepard, Caitlin; Oo, Adrian; Arizaga, Fidel; Kapoor-Vazirani, Priya; Persaud, Mirjana; Yu, Corey H.; Kim, Dong Hyun; Schinazi, Raymond F.; Ivanov, Dmitri N.; Díaz-Griffero, Felipe; Yu, David S.; Xiong, Yong; Kim, Baek

doi:10.1016/j.jbc.2021.101170

Cited by 9 publications

(8 citation statements)

References 71 publications

(154 reference statements)

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“…While the SAMHD1 protein was detected at 72 kDa by immunoblotting in normal 48BR cells, this band was not detectable in the patient's CS213NG cells (Figure 2B). This result is consistent with previous reports describing the instability nature of the missense variant, p. Y155C, in vitro (34), or in leukemia patients' cells with this mutation (33).…”

Section: Exome Sequencing Identifies Loss Of Function Variants In Samhd1supporting

confidence: 93%

Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test

et al. 2022

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Aicardi–Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.

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Section: Exome Sequencing Identifies Loss Of Function Variants In Samhd1supporting

confidence: 93%

Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test

et al. 2022

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“…In addition, we did not find a significant correlation between mutations and SAMHD1 expression in MCL and between mutations and clinical outcome. Although the newly found mutations had no obvious effect on the prognosis of MCL patients, some SAMHD1 mutations previously reported were associated with chronic lymphocytic (B-cell) leukemia development (11) and changed its dNTPase activity (39). It will be very interesting to study the impact of these four new mutations we found in this study on the structure and function of the SAMHD1 molecule.…”

Section: Discussionmentioning

confidence: 60%

SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients

et al. 2021

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SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (p = 0.023) and shorter overall survival (p = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an in vitro study using the siRNA technique. Silencing the SAMHD1 gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with SAMHD1 knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the SAMHD1 gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.

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“…dNTP hydrolase, nuclease recruitment, innate immunity suppression, nucleic acid binding), it is difficult to hypothesise the outcome for cancer biology, given the impact of the loss of SAMHD1 can be hypothesised to have different outcomes depending upon the biological role in question. This approach was applied in a recent study characterising the colon cancer and leukaemia‐associated R366C/H mutant, and showed that while this mutation retains noncatalytic roles of SAMHD1, the dNTPase activity is abolished [ 130 ]. Accordingly, this mutation could contribute to elevated dNTP pools, which are commonly reported in cancer cells [ 131 ].…”

Section: Samhd1mentioning

confidence: 99%

Targeting the DNA damage response and repair in cancer through nucleotide metabolism

Helleday

Rudd

2022

Molecular Oncology

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The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1.

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Structural and functional characterization explains loss of dNTPase activity of the cancer-specific R366C/H mutant SAMHD1 proteins

Cited by 9 publications

References 71 publications

Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test

Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test

SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients

Targeting the DNA damage response and repair in cancer through nucleotide metabolism

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