The maelstrom spermatogenic transposon silencer (MAEL) function in postmeiotic germ cells remains unclear, and its protein localization in human testis and spermatozoa awaits determination. This study aims to clarify the MAEL expression in human spermatogenesis and to explore its role in sperm function.Twenty-seven asthenozoospermic men, 40 normozoospermic controls, and three obstructive azoospermic men were enrolled. The transcripts of MAEL in the seminiferous epithelium and MAEL downstream targets were identified by bioinformatics analysis. MAEL protein expression in human testis and ejaculated sperms were examined by immunohistochemical and immunogold staining, respectively. The roles of MAEL in mitochondria function were investigated by siRNA knockdown in human H358 cells. The association between MAEL protein levels and clinical sperm features was evaluated.Abundant MAEL was expressed in spermatid and spermatozoa of the human testis. Remarkably, MAEL was located in the mitochondria of ejaculated sperm, and bioinformatics analysis identified GPX4 and UBL4B as MAEL's downstream targets. Knockdown of MAEL sabotaged mitochondria function and reduced adenosine triphosphate (ATP) production in H358 cells. MAEL, GPX4, and UBL4B expression levels were significantly decreased in asthenozoospermic sperms than in controls. The MAEL protein levels were positively correlated with GPX4 and UBL4B in human sperm. Total motile sperm count (TMSC) was positively correlated with protein levels of MAEL, GPX4, and UBL4B in ejaculated sperms.We highlight prominent MAEL expression in the intratesticular spermatid and the mitochondria of ejaculated spermatozoa. MAEL directly binds to GPX4 and UBL4B, and loss of MAEL induces mitochondrial dysfunction. MAEL-mitochondrial function-motility relationship might advance our understanding of the causes of asthenozoospermia.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. Here, we showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.
Abstract Ferroptosis is an iron-dependent oxidative cell death with accumulation of lipid peroxidation and abnormal morphology of mitochondria. Although previous studies have shown that ferroptosis inducers have therapeutic potentials in several treatment-naive and drug-resistant cancer types, lacking systematic analysis of the ferroptosis sensitivity in different cancer types makes it difficult to know which cancer type is suitable for clinical usage and critical regulator determining the ferroptosis sensitivity during cancer progression is still not clear. In this study, colon cancer was identified as one of the ferroptosis-insensitive cancer types by dry and wet bench analyses. Importantly, our large-scale analysis also showed that NUDT16L1 was a novel ferroptosis repressor and overexpressed in colon cancer clinical specimens. Similar findings are also observed in the chemical-induced and genetic mouse models of colon cancer. Furthermore, NUDT16L1 loss-of-function and gain-of-function cell models and its conditional knock-in and knock-out mouse models are used to prove its crucial role in the development of colon cancer. In addition, loss of NUDT16L1 induced several key ferroptosis characteristics and impairment of mitochondrial functions while its restoration attenuated those phenomena in colon cancer cells. Mechanistically, our RNA-Seq and RIP-Seq analyses shown that NUDT16L1 directly interacted and positively regulated several crucial negative regulators of ferroptosis. More interestingly, loss of NUDT16L1 not only restores the sensitivity of ferroptosis inducer but also impairs the function of mitochondria. Finally, a specific NUDT16L1 inhibitor was shown to not only repress colon cancer growth in vitro and in vivo but also induce the ferroptosis in colon cancer. In conclusion, this is the first study to demonstrate that overexpression of NUDT16L1 promotes colon cancer progression by inhibition of ferroptosis and maintenance proper function of mitochondria. Furthermore, specific NUDT16L1 inhibitor might be a promising therapeutic strategy for colon cancer patient in the future. Citation Format: Yi-Syuan Lin, Ya-Chuan Tsai, Chia-Jung Li, Tzu-Tang Wei, Ya-Na Wu, Shang-Rung Wu, Shin-Chin Lin, Shaw-Jenq Tsai, Shih-Chieh Lin. NUDT16L1 promotes colon cancer progression via inhibition of ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1372.
Metastasis is the main cause of death in many cancers including colorectal cancer (CRC); however, the underlying mechanisms responsible for metastatic progression remain largely unknown. We found that nuclear TYRO3 receptor tyrosine kinase is a strong predictor of poor overall survival in patients with CRC. The metastasis-promoting function of nuclear TYRO3 requires its kinase activity and matrix metalloproteinase-2 (MMP-2)-mediated cleavage but is independent of ligand binding. Using proteomic analysis, we identified bromodomain-containing protein 3 (BRD3), an acetyl-lysine reading epigenetic regulator, as one of nuclear TYRO3's substrates. Chromatin immunoprecipitation-sequencing data reveal that TYRO3-phosphorylated BRD3 regulates genes involved in anti-apoptosis and epithelial-mesenchymal transition. Inhibition of MMP-2 or BRD3 activity by selective inhibitors abrogates nuclear TYRO3-induced drug resistance and metastasis in organoid culture and in orthotopic mouse models. These data demonstrate that MMP-2/TYRO3/BRD3 axis promotes the metastasis of CRC, and blocking this signaling cascade is a promising approach to ameliorate CRC malignancy.
Intracellular calcium (Ca2+) has been reported to regulate transcription factor activity and cancer development, but how it affects the function of Forkhead box protein M1 (FOXM1), a crucial transcription factor and key oncogene participating in tumorigenesis, remains unclear. Here, we investigated the regulatory role of Ca2+ on FOXM1 and found that Ca2+ depletion caused the distribution of FOXM1 to aggregate on the nuclear envelope, which was also observed in many cell lines. Further experiments revealed that sequestrated FOXM1 colocalized with lamin B in the inner nuclear membrane (INM) and was affected by the activity of nuclear export protein exportin 1 (XPO1). To investigate how intracellular Ca2+ affects FOXM1, we found that among the posttranscriptional modifications, only SUMOylation of FOXM1 showed a pronounced increase under reduced Ca2+, and suppressed SUMOylation rescued FOXM1 sequestration. In addition, Ca2+-dependent SUMOylated FOXM1 appeared to enhance the G2/M transition of the cell cycle and decrease cell apoptosis. In conclusion, our findings provide a molecular basis for the relationship between Ca2+ signaling and FOXM1 regulation, and we look to elucidate Ca2+-dependent FOXM1 SUMOylation-related biological functions in the future.
Recently, the requirement of storing digital data has been growing rapidly; however, the conventional storage medium cannot satisfy these huge demands. Fortunately, thanks to biological technology development, storing digital data into deoxyribonucleic acid (DNA) has become possible in recent years. Furthermore, because of the attractive features (e.g., high storing density, long-term durability, and stability), DNA storage has been regarded as a potential alternative storage medium to store massive digital data in the future. Nevertheless, reading and writing digital data over DNA requires a series of extremely time-consuming processes (i.e., DNA sequencing and DNA synthesis). More specifically, among the two costs, the writing cost is the predominant cost of a DNA data storage system. Therefore, to enable efficient DNA storage, this article proposes an index management scheme for reducing the number of accesses to DNA storage. Additionally, this article introduces a new DNA data encoding format with VERA (Version Editing Recovery Approach) to reduce the total writing bits while inserting and deleting the data. To the best of our knowledge, this work is the first work to provide a total data management solution for DNA storage. According to the experimental results, the proposed design with VERA can reduce the cost by 77% and improve the performance by 71% compared to the append-only methods.
As storage capacity demands escalate, Shingled Magnetic Recording (SMR) disks have grown increasingly popular in the storage device market [1]. However, the overlapping tracks inherent to SMR disk drives cause write amplification during random writes, a phenomenon that degrades performance relative to traditional Perpendicular Magnetic Recording (PMR) disk drives [2]. While Skylight has offered a solution to this issue [7], we present a novel approach in MSMR, a mode-switching scheme for SMR disks. MSMR optimizes storage space by intelligently allocating data to either PMR or SMR based on predicted update frequency. This adaptive strategy enables disks to meet storage capacity needs and performance efficiency objectives. Upon evaluation, MSMR has exhibited a significant reduction in write amplification, averagely lowering total writes by 99.39% compared to Native SMR. Thus, MSMR presents an efficient solution for boosting performance while minimizing write amplification.
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