A long-standing mystery surrounding ataxia-telangiectasia is why it is mainly cerebellar neurons, Purkinje cells in particular, that appear vulnerable to ATM deficiency. Here we present data showing that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human ataxia-telangiectasia and Atm(-/-) mouse cerebellar Purkinje cells. We further show that TET1, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responds to DNA damage and manipulation of TET1 activity directly affects the DNA damage signalling and ATM-deficient neuronal cell cycle re-entry and death. Quantitative genome-wide analysis of 5hmC-containing sequences shows that in ATM deficiency there is a cerebellum- and Purkinje cell-specific shift in 5hmC enrichment in both regulatory elements and repeated sequences. Finally, we verify that TET1-mediated 5hmC production is linked to the degenerative process of Purkinje cells and behavioural deficits in Atm(-/-) mice. Taken together, the selective loss of 5hmC plays a critical role in driving Purkinje cell vulnerability in ATM deficiency.

Nematode-trapping fungi (NTF) are potential biological control agents against plant- and animal-parasitic nematodes. These fungi produce diverse trapping devices (traps) to capture, kill, and digest nematodes as food sources. Most NTF can live as both saprophytes and parasites. Traps are not only the weapons that NTF use to capture and infect nematodes, but also an important indicator of their switch from a saprophytic to a predacious lifestyle. Formation of traps and their numbers are closely related to the nematicidal activity of NTF, so the mechanisms governing trap formation have become a focus of research on NTF. Recently, much progress has been made in our understanding of trap formation, evolution, and the genome, proteome and transcriptome of NTF. Here we provide a comprehensive overview of recent advances in research on traps of NTF. Various inducers of trap formation, trap development, structural properties and evolution of traps are summarized and discussed. We specifically discuss the latest studies of NTF based on genomic, proteomic and transcriptomic analyses.

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An efficient, accurate, and timely DNA damage response (DDR) is crucial for the maintenance of genome integrity. Here, we report that ten-eleven translocation dioxygenase (TET) 3-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in response to ATR-dependent DDR regulates DNA repair. ATR-dependent DDR leads to dynamic changes in 5hmC levels and TET3 enzymatic activity. We show that TET3 is an ATR kinase target that oxidizes DNA during ATR-dependent DNA damage repair. Modulation of TET3 expression and activity affects DNA damage signaling and DNA repair and consequently cell death. Our results provide novel insight into ATR-mediated DDR, in which TET3-mediated DNA demethylation is crucial for efficient DNA repair and maintenance of genome stability.

Breast cancer stem cells (BCSCs) are responsible for resistance to chemotherapy, high degree of metastasis, and poor prognosis, especially in triple‐negative breast cancer (TNBC). The CD24 low CD44 high and high aldehyde dehydrogenase 1 (ALDH1) cell subpopulation (CD24 low CD44 high ALDH1 + ) exhibit very high tumor initiating capacity. In the current study, the upregulated genes are analyzed in both CD24 low CD44 high and ALDH1 + cell populations at single‐cell resolution, and a highly expressed membrane protein, SGCE, is identified in both BCSC populations. Further results show that SGCE depletion reduces BCSC self‐renewal, chemoresistance, and metastasis both in vitro and in vivo, partially through affecting the accumulation of extracellular matrix (ECM). For the underlying mechanism, SGCE functions as a sponge molecule for the interaction between epidermal growth factor receptor (EGFR) and its E3 ubiquitination ligase (c‐Cbl), and thus inhibits EGFR lysosomal degradation to stabilize the EGFR protein. SGCE knockdown promotes sensitivity to EGFR tyrosine kinase inhibitors (TKIs), providing new clues for deciphering the current failure of targeting EGFR in clinical trials and highlighting a novel candidate for BCSC stemness regulation.

Breast cancer patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem-like cells (BCSCs). Numerous studies have reported that high levels of inflammatory factors, including tumor necrosis factor alpha (TNF-α), promote BCSCs. However, the mechanism by which tnf-α promotes BCSCs is unclear. In this study, we demonstrate that TNF-α up-regulates TAZ, a transcriptional co-activator promoting BcSc self-renewal capacity in human breast cancer cell lines. Depletion of TAZ abrogated the increase in BCSCs mediated by TNF-α. TAZ is induced by TNF-α through the non-canonical nf-κB pathway, and our findings suggest that TAZ plays a crucial role in inflammatory factor-promoted breast cancer stemness and could serve as a promising therapeutic target.Breast cancer is one of the most common malignances and a serious threat to women's health worldwide 1 . Inflammation, especially chronic inflammation, plays an important role in cancer initiation and progression 2 . Tumor cells and a variety of leukocytes attracted by tumor cells produce various cytokines and chemokines that affect cancer development 3 . In general, cytokines are divided into two groups. One group comprises pro-inflammatory factors, including tumor necrosis factor alpha (TNF-α), IL1β, IL-6, etc 4,5 . The other group is made of anti-inflammatory factors, including IL-10, IL-13, etc 5 . High levels of pro-inflammatory cytokines promote tumor growth and migration, enhance the survival of malignant cells, suppress adaptive immune responses, and cause resistance to hormones and chemotherapeutic agents 6,7 . Non-steroidal anti-inflammatory drugs decrease the risk for developing and the risk of mortality in breast cancer 3 . Characterization of the mechanisms by which inflammatory cytokines promote breast cancer development may offer new therapeutic opportunities.TNF-α is a well-documented pro-inflammatory cytokine that is up-regulated in breast cancer, and high levels of TNF-α are associated with breast cancer recurrence 8,9 . Additionally, TNF-α levels are positively correlated with tumor grade in serous ovarian tumors 10 . Moreover, TNF-α knockout mice are less susceptible to DMBA-or TPA-induced skin tumors 8 . TNF-α binds to two different receptors, TNF-α receptor 1 and 2 (TNFR1/2), to activate the NF-κB signaling pathway 11,12 . TNFR1/2 activates IKK and subsequently causes IκBα phosphorylation, ubiquitination, and degradation, leading to p65, RelB or p50 translocation to the nucleus. In addition to the canonical NF-κB pathway, TNF-α is able to activate JNK, MAPKs, AKT, and the non-canonical NF-κB pathway [13][14][15] . TNF-α up-regulates over 400 inflammatory genes, including cell-adhesion molecules, anti-apoptotic proteins, inflammatory cytokines, and chemokines 16,17 .Ginalu Storci et al. reported that TNF-α increases the proportion of breast cancer stem-like cells (BCSCs) through NF-κB/HIF1α/Slug 18 . BCSCs are a small subpopulation of the primary breast tumor with differentiation and self-renewal capacities that are re...

Proteins that serve as regulator of G protein signaling (RGS) primarily function as GTPase accelerators that promote GTP hydrolysis by the Gα subunits, thereby inactivating the G protein and rapidly switching off G protein-coupled signaling pathways. Since the first RGS protein was identified from the budding yeast Saccharomyces cerevisiae, more than 30 RGS and RGS-like proteins have been characterized from several model fungi, such as Aspergillus nidulans, Beauveria bassiana, Candida albicans, Fusarium verticillioides, Magnaporthe oryzae, and Metarhizium anisopliae. In this review, the partial biochemical properties and functional domains of RGS and RGS-like proteins were predicted and compared, and the roles of RGS and RGS-like proteins in different fungi were summarized. Moreover, the phylogenetic relationship among RGS and RGS-like proteins from various fungi was analyzed and discussed.

Nematode-trapping fungi can secrete many extracellular hydrolytic enzymes such as serine proteases and chitinases to digest and penetrate nematode/egg-cuticles. However, little is known about the structure and function of chitinases in these fungi. In this study, 16 ORFs encoding putative chitinases, which all belong to glycoside hydrolase (GH) family 18, were identified from the Arthrobotrys oligospora genome. Bioinformatics analyses showed that these 16 putative chitinases differ in their functional domains, molecular weights and pI. Phylogenetic analysis grouped these A. oligospora chitinases into four clades: clades I, II, III and IV, respectively, including an A. oligospora-specific subclade (Clade IV-B) that contained high-molecular weight chitinases (≥100 kDa). Transcriptional analysis of A. oligospora chitinases suggested that the expression of most chitinases was repressed by carbon starvation, and all chitinases were up-regulated under nitrogen starvation. However, chitinase AO-190 was up-regulated under carbon and/or nitrogen starvation. Moreover, several chitinases (such as AO-59, AO-190 and AO-801) were up-regulated in the presence of chitinous substrates or a plant pathogenic fungus, indicating that they could play a role in biocontrol applications of A. oligospora. Our results provided a basis for further understanding the functions, diversities and evolutionary relationships between chitinase genes in nematode-trapping fungi.