Nuclear Overexpression of SAMHD1 Induces M Phase Stalling in Hepatoma Cells and Suppresses HCC Progression by Interacting with the Cohesin Complex DOI Creative Commons
Juntang Shao, Wei Wang, Shiyu Li

и другие.

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Дек. 16, 2024

Abstract Emerging evidence suggests that the sterile alpha‐motif (SAM) and histidine‐aspartate (HD) domain‐containing protein 1 (SAMHD1) is implicated in various cancers, including hepatocellular carcinoma (HCC). However, its precise role tumor cells underlying mechanisms remain unclear. This study aimed to investigate expression patterns, prognostic values, functional of SAMHD1 HCC progression. We constructed liver tissue microarrays using paired paratumor specimens from 187 patients with primary HCC. Our findings indicate nuclear levels are increased tumors compared tissues. Moreover, decline advanced stages, higher staining correlating favorable outcomes. Hepatocyte‐specific knockout mice, generated by crossing fl/fl mice Alb‐cre showed accelerated progression a diethylnitrosamine (DEN)‐induced model. In hepatoma cell lines, overexpression inhibited proliferation stalling mitosis, independent deoxynucleotide triphosphohydrolase (dNTPase) function. Mechanistically, interacts cohesin complex nucleus, enhancing sister chromatid cohesion during division, which delays metaphase suggest plays critical slowing regulating highlighting potential as therapeutic target manipulating dynamics.

Язык: Английский

Genetic links between ovarian ageing, cancer risk and de novo mutation rates DOI Creative Commons
Stasa Stankovic, Saleh Shekari, Qin Qin Huang

и другие.

Nature, Год журнала: 2024, Номер 633(8030), С. 608 - 614

Опубликована: Сен. 11, 2024

Язык: Английский

Процитировано

20
SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs DOI Creative Commons
Claudia McCown, Corey H. Yu, Dmitri N. Ivanov

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 17, 2025

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism SAMHD1, which involves dNTP binding at allosteric sites transient tetramerization. Our findings reveal tetramerization alone insufficient to promote hydrolysis; instead, requires an inactive tetrameric intermediate with partially occupied sites. The equilibrium between active states regulates activity, driven by dissociation additional ligands preassembled tetramer. Furthermore, catalytic efficiency, but not specificity, modulated identity dNTPs occupying We show how this regulation shapes deoxynucleotide homeostasis balancing production SAMHD1-catalyzed depletion. Notably, exhibits distinct functionality, term facilitated depletion, whereby increased biosynthesis certain enhances depletion others. regulatory relationship different sheds light on emerging role biology implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Язык: Английский

Процитировано

3
Targeting the DNA damage response and repair in cancer through nucleotide metabolism DOI Creative Commons
Thomas Helleday, Sean G. Rudd

Molecular Oncology, Год журнала: 2022, Номер 16(21), С. 3792 - 3810

Опубликована: Май 18, 2022

The exploitation of the DNA damage response and repair proficiency cancer cells is an important anticancer strategy. replication are dependent upon supply deoxynucleoside triphosphate (dNTP) building blocks, which produced maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic lesions in cells. These same also activate antimetabolites, group chemotherapies that disrupt both metabolism Thus, dNTP enzymes targeted refine use chemotherapeutics, many remain standard care common cancers. In this review article, we will discuss approaches exemplified MTH1, MTHFD2 SAMHD1. © 2022 Authors. Molecular Oncology published John Wiley & Sons Ltd on behalf Federation European Biochemical Societies.

Язык: Английский

Процитировано

28
SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks DOI Creative Commons

Priya Kapoor-Vazirani,

Sandip Kumar Rath, Xu Liu

и другие.

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Ноя. 7, 2022

Abstract Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) has a dNTPase-independent function in promoting DNA end resection to facilitate double-strand break (DSB) repair by homologous recombination (HR); however, it is not known if upstream signaling events govern this activity. Here, we show that SAMHD1 deacetylated the SIRT1 sirtuin deacetylase, facilitating its binding with ssDNA at DSBs, promote HR. complexes deacetylates conserved lysine 354 (K354) specifically response DSBs. K354 deacetylation promotes HR but tetramerization or dNTPase Mechanistically, recruitment DSBs which turn facilitates CtIP binding, leading promotion of genome integrity. These findings define mechanism governing stability.

Язык: Английский

Процитировано

22
Understanding the interplay between dNTP metabolism and genome stability in cancer DOI Creative Commons
Miriam Yagüe-Capilla, Sean G. Rudd

Disease Models & Mechanisms, Год журнала: 2024, Номер 17(8)

Опубликована: Авг. 1, 2024

ABSTRACT The size and composition of the intracellular DNA precursor pool is integral to maintenance genome stability, this relationship fundamental our understanding cancer. Key aspects carcinogenesis, including elevated mutation rates induction certain types damage in cancer cells, can be linked disturbances deoxynucleoside triphosphate (dNTP) pools. Furthermore, approaches treat heavily exploit metabolic interplay between dNTP pool, with a long-standing example being use antimetabolite-based therapies, strategy continues show promise development new targeted therapies. In Review, we compile current knowledge on both causes consequences perturbations together their impact stability. We outline several outstanding questions remaining field, such as role catabolism stability expansion. Importantly, detail how mechanistic these processes utilised aim providing better informed treatment options patients

Язык: Английский

Процитировано

4
SAMHD1 silencing cooperates with radiotherapy to enhance anti-tumor immunity through IFI16-STING pathway in lung adenocarcinoma DOI Creative Commons

Yangyi Li,

Yuke Gao,

Xueping Jiang

и другие.

Journal of Translational Medicine, Год журнала: 2022, Номер 20(1)

Опубликована: Дек. 29, 2022

Abstract Background Sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) is a DNA end resection factor, which involved in damage repair innate immunity. However, the role of SAMHD1 anti-tumor immunity still unknown. This study investigated effects on stimulator interferon genes (STING)-type I (IFN) pathway radiation-induced immune responses. Methods The roles activation cytosolic sensing STING lung adenocarcinoma (LUAD) cells were with flow cytometry, immunofluorescence, immunoblotting qPCR. combined silencing radiation tumor cell growth also evaluated colony formation CCK8 assay. Lewis cancer mouse model was used to evaluate efficiency radiotherapy vivo. Macrophage M1 polarization cytotoxic T infiltration cytometry. Results single-stranded (ssDNA) accumulated cytosol SAMHD1-deficient cells, accompanied by upregulated sensor IFN-γ-inducible 16 (IFI16) activated pathway. translocation IFI16 from nucleus detected cells. acquired STING-IFN-I LUAD promoted macrophage vitro. synergized activate ssDNA-STING-IFN-I pathway, inhibit proliferation, promote apoptosis regulate cycle. cooperated increase CD86 + MHC-II high proportion CD8 Conclusions deficiency induced IFN-I production through IFI16-STING Moreover, downregulation enhance responses infiltration. Combination inhibition may be potentially therapeutic strategy for patients.

Язык: Английский

Процитировано

15
Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases DOI Creative Commons
Jonathan Mitchell, Niedzica Camacho, Patrick R. Shea

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 10, 2024

The etiology of prostate cancer, the second most common cancer in men globally, has a strong heritable component. While rare coding germline variants several genes have been identified as risk factors from candidate gene and linkage studies, exome-wide spectrum causal remains to be fully explored. To more comprehensively address their contribution, we analysed data 37,184 cases 331,329 male controls five cohorts with exome/genome sequencing one cohort imputed array population enriched low-frequency deleterious variants. Our gene-level collapsing analysis revealed that damaging

Язык: Английский

Процитировано

3
Elevated SAMD3 expression in T cells predicts improved survival in pancreatic ductal adenocarcinoma patients DOI Creative Commons
Lingyi Fu, Enliang Zhou, Shuo Li

и другие.

Cancer Immunology Immunotherapy, Год журнала: 2025, Номер 74(3)

Опубликована: Фев. 1, 2025

Pancreatic ductal adenocarcinoma (PDAC) has an immune-suppressive tumor microenvironment that contributes to resistance immunotherapy. This study aimed demonstrate elevated sterile alpha motif domain-containing protein 3 (SAMD3) expression in effector CD8+ T cells was associated with improved survival PDAC patients. We investigated the heterogeneity and gene profiles of using a single-cell RNA sequencing (sc-RNA-seq) dataset comprised human samples. SAMD3 mRNA further evaluated tumor-specific OT-I/ovalbumin (OVA) mouse model. levels their clinical significance were via immunohistochemistry (IHC) analysis. highly expressed cytotoxic cells, significantly downregulated during cell exhaustion. positively correlated function. In patients, high overall (OS), disease-free (DFS), infiltration. A patient exhibiting partial response combination immunotherapy also showed cells. is biomarker function, predicting survival. These findings highlight potential precision approaches for treating PDAC.

Язык: Английский

Процитировано

0
Machine learning approach to predict prognosis and immunotherapy responses in colorectal cancer patients DOI Creative Commons
Zhen Liu, Yu Dou, Pengyan Xia

и другие.

hLife, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
Evaluation of the clinical significance of BTG1 gene expression and pepsinogen in serum and cancerous tissue and gastric atrophy DOI
Yousef Paridar,

Homa Hosseinpour,

Maysam Mard‐Soltani

и другие.

Archives of Physiology and Biochemistry, Год журнала: 2025, Номер unknown, С. 1 - 10

Опубликована: Фев. 23, 2025

Introduction This study aimed to assess the expression changes of BTG1, PGI, and PGII in tissues serum patients with gastric cancer, atrophic gastritis, healthy individuals.

Язык: Английский

Процитировано

0