2015 Vol. 6(3)

CRISPR/Cas9 and TALE: beyond cut and paste
Liping Deng, Ruotong Ren, Jun Wu, Keiichiro Suzuki, Juan Carlos Izpisua Belmote, Guang-Hui Liu
2015, 6(3): 157-159. doi: 10.1007/s13238-015-0137-5
Nuclease-based genome editing has proven to be a powerful and promising tool for disease modeling and gene therapy. Recent advances in CRISPR/Cas and TALE indicate that they could also be used as a targeted regulator of gene expression, as well as being utilized for illuminating specific chromosomal structures or genomic regions.
The role of Smad7 in oral mucositis
Li Bian, Gangwen Han, Carolyn W. Zhao, Pamela J. Garl, Xiao-Jing Wang
2015, 6(3): 160-169. doi: 10.1007/s13238-014-0130-4
Oral mucositis, a severe oral ulceration, is a common toxic effect of radio-or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. Among cancer patients, at least 40% and up to 70%, of individuals treated with standard chemotherapy regimens or upper-body radiation, develop oral mucositis. To date, there is no FDA approved drug to treat oral mucositis in cancer patients. The key challenges for oral mucositis treatment are to repair and protect ulcerated oral mucosa without promoting cancer cell growth. Oral mucositis is the result of complex, multifaceted pathobiology, involving a series of signaling pathways and a chain of interactions between the epithelium and submucosa. Among those pathways and interactions, the activation of nuclear factor-kappa B (NF-κB) is critical to the inflammation process of oral mucositis. We recently found that activation of TGFβ (transforming growth factor β) signaling is associated with the development of oral mucositis. Smad7, the negative regulator of TGFβ signaling, inhibits both NF-κB and TGFβ activation and thus plays a pivotal role in the prevention and treatment of oral mucositis by attenuating growth inhibition,apoptosis,and inflammation while promoting epithelial migration. The major objective of this review is to evaluate the known functions of Smad7, with a particular focus on its molecular mechanisms and its function in blocking multiple pathological processes in oral mucositis.
Innate endogenous adjuvants prime to desirable immune responses via mucosal routes
Xiaoguang Wang, Delong Meng
2015, 6(3): 170-184. doi: 10.1007/s13238-014-0125-1
Vaccination is an effective strategy to prevent infectious or immune related diseases, which has made remarkable contribution in human history. Recently increasing attentions have been paid to mucosal vaccination due to its multiple advantages over conventional ways. Subunit or peptide antigens are more reasonable immunogens for mucosal vaccination than live or attenuated pathogens, however adjuvants are required to augment the immune responses. Many mucosal adjuvants have been developed to prime desirable immune responses to different etiologies. Compared with pathogen derived adjuvants, innate endogenous molecules incorporated into mucosal vaccines demonstrate prominent adjuvanticity and safety. Nowadays, cytokines are broadly used as mucosal adjuvants for participation of signal transduction of immune responses, activation of innate immunity and polarization of adaptive immunity. Desired immune responses are promptly and efficaciously primed on basis of specific interactions between cytokines and corresponding receptors. In addition, some other innate molecules are also identified as potent mucosal adjuvants. This review focuses on innate endogenous mucosal adjuvants,hoping to shed light on the development of mucosal vaccines.
Research articles
Structure of precursor microRNA's terminal loop regulates human Dicer's dicing activity by switching DExH/D domain
Zhongmin Liu, Jia Wang, Gang Li, Hong-Wei Wang
2015, 6(3): 185-193. doi: 10.1007/s13238-014-0124-2
Almost all pre-miRNAs in eukaryotic cytoplasm are recognized and processed into double-stranded microRNAs by the endonuclease Dicer protein comprising of multiple domains. As a key player in the small RNA induced gene silencing pathway, the major domains of Dicer are conserved among different species with the exception of the N-terminal components. Human Dicer's N-terminal domain has been shown to play an autoinhibitory function of the protein's dicing activity. Such an auto-inhibition can be released when the human Dicer protein dimerizes with its partner protein, such as TRBP, PACT through the N-terminal DExH/D (ATPasehelicase) domain. The typical feature of a pre-miRNA contains a terminal loop and a stem duplex, which bind to human Dicer's DExH/D (ATPase-helicase) domain and PAZ domain respectively during the dicing reaction. Here, we show that pre-miRNA's terminal loop can regulate human Dicer's enzymatic activity by interacting with the DExH/D (ATPase-helicase) domain. We found that various editing products of pre-miR-151 by the ADAR1P110 protein, an A-to-I editing enzyme that modifies pre-miRNAs sequence, have different terminal loop structures and different activity regulatory effects on human Dicer. Single particle electron microscopy reconstruction revealed that pre-miRNAs with different terminal loop structures induce human Dicer's DExH/D (ATPase-helicase) domain into different conformational states, in correlation with their activity regulatory effects.
Essential role of the iron-sulfur cluster binding domain of the primase regulatory subunit Pri2 in DNA replication initiation
Lili Liu, Mingxia Huang
2015, 6(3): 194-210. doi: 10.1007/s13238-015-0134-8
DNA primase catalyzes de novo synthesis of a short RNA primer that is further extended by replicative DNA polymerases during initiation of DNA replication. The eukaryotic primase is a heterodimeric enzyme comprising a catalytic subunit Pri1 and a regulatory subunit Pri2. Pri2 is responsible for facilitating optimal RNA primer synthesis by Pri1 and mediating interaction between Pri1 and DNA polymerase α for transition from RNA synthesis to DNA elongation. All eukaryotic Pri2 proteins contain a conserved C-terminal iron-sulfur (Fe-S) cluster-binding domain that is critical for primase catalytic activity in vitro. Here we show that mutations at conserved cysteine ligands for the Pri2 Fe-S cluster markedly decrease the protein stability, thereby causing S phase arrest at the restrictive temperature. Furthermore, Pri2 cysteine mutants are defective in loading of the entire DNA pol α-primase complex onto early replication origins resulting in defective initiation. Importantly, assembly of the Fe-S cluster in Pri2 is impaired not only by mutations at the conserved cysteine ligands but also by increased oxidative stress in the sod1Δ mutant lacking the Cu/Zn superoxide dismutase. Together these findings highlight the critical role of Pri2's Fe-S cluster domain in replication initiation in vivo and suggest a molecular basis for how DNA replication can be influenced by changes in cellular redox state.
Bayesian localization microscopy based on intensity distribution of fluorophores
Fan Xu, Mingshu Zhang, Zhiyong Liu, Pingyong Xu, Fa Zhang
2015, 6(3): 211-220. doi: 10.1007/s13238-015-0133-9
Super-resolution microscopy techniques have overcome the limit of optical diffraction. Recently, the Bayesian analysis of Bleaching and Blinking data (3B) method has emerged as an important tool to obtain super-resolution fluorescence images. 3B uses the change in information caused by adding or removing fluorophores in the cell to fit the data. When adding a new fluorophore, 3B selects a random initial position, optimizes this position and then determines its reliability. However, the fluorophores are not evenly distributed in the entire image region, and the fluorescence intensity at a given position positively correlates with the probability of observing a fluorophore at this position. In this paper, we present a Bayesian analysis of Bleaching and Blinking microscopy method based on fluorescence intensity distribution (FID3B). We utilize the intensity distribution to select more reliable positions as the initial positions of fluorophores. This approach can improve the reconstruction results and significantly reduce the computational time. We validate the performance of our method using both simulated data and experimental data from cellular structures. The results confirm the effectiveness of our method.
I-GSEA4GWAS v2: a web server for functional analysis of SNPs in trait-associated pathways identified from genome-wide association study
Kunlin Zhang, Suhua Chang, Liyuan Guo, Jing Wang
2015, 6(3): 221-224. doi: 10.1007/s13238-014-0114-4
Crystal structure of human Fanconi-associated nuclease 1
Peng-xian Yan, Yan-gao Huo, Tao Jiang
2015, 6(3): 225-228. doi: 10.1007/s13238-014-0128-y
Nano-size uni-lamellar lipodisq improved in situ auto-phosphorylation analysis of E. coli tyrosine kinase using 19F nuclear magnetic resonance
Dong Li, Juan Li, Yonglong Zhuang, Longhua Zhang, Ying Xiong, Pan Shi, Changlin Tian
2015, 6(3): 229-233. doi: 10.1007/s13238-014-0129-x

Current Issue

March, 2019

Volume 10, Issue 3

Pages 157-233

About the cover

Metastasis is the leading cause of human cancer deaths.Unfortunately, no approved drugs are available for antimetastatic treatment. In this study, high-throughputsequencing-based high-throughput screening (HTS2) anda breast cancer lung metastasis (BCLM)-associated genesignature were combined to discover anti-metastatic drugs.After screening of thousands of compounds, Shao et al.identifed Ponatinib as a BCLM inhibitor. Ponatinib signifcantlyinhibited the migration and mammosphere formation of breastcancer cells in vitro and blocked BCLM in multiple mousemodels. This study may facilitate the therapeutic treatment ofBCLM as well as other metastases.

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