Transient Activation of Autophagy via Sox2-Mediated Suppression of mTOR Is an Important Early Step in Reprogramming to Pluripotency

SummaryAutophagy is an essential cellular mechanism that degrades cytoplasmic proteins and organelles to recycle their components. Here we show that autophagy is required for reprogramming of somatic cells to form induced pluripotent stem cells (iPSCs). Our data indicate that mammalian target of rapamycin (mTOR) is downregulated by Sox2 at an early stage of iPSC generation and that this transient downregulation of mTOR is required for reprogramming to take place. In the absence of Sox2, mTOR remains at a high level and inhibits autophagy. Mechanistically, Sox2 binds to a repressive region on the mTOR promoter and recruits the NuRD complex to mediate transcriptional repression. We also detected enhanced autophagy at the four- to eight-cell stage of embryonic development, and a similar Sox2 and mTOR-mediated regulatory pathway seems to operate in this context as well. Thus, our findings reveal Sox2-dependent temporal regulation of autophagy as a key step in cellular reprogramming processes

Noncoding RNAs in tumorigenesis and tumor therapy

Tumorigenesis is a complicated process in which numerous modulators are involved in different ways. Previous studies have focused primarily on tumor-associated protein-coding genes such as oncogenes and tumor suppressor genes, as well as their associated oncogenic pathways. However, noncoding RNAs (ncRNAs), rising stars in diverse physiological and pathological processes, have recently emerged as additional modulators in tumorigenesis. In this review, we focus on two typical kinds of ncRNAs: long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs). We describe the molecular patterns of ncRNAs and focus on the roles of ncRNAs in cancer stem cells (CSCs), tumor cells, and tumor environmental cells. CSCs are a small subset of tumor cells and are generally considered to be cells that initiate tumorigenesis, and dozens of ncRNAs have been defined as critical modulators in CSC maintenance and oncogenesis. Moreover, ncRNAs are widely involved in oncogenetic processes, including sustaining proliferation, resisting cell death, genome instability, metabolic disorders, immune escape and metastasis. We also discuss the potential applications of ncRNAs in tumor diagnosis and therapy. The progress in ncRNA research greatly improves our understanding of ncRNAs in oncogenesis and provides new potential targets for future tumor therapy

HMG2 Interacts with the Nucleosome Assembly Protein SET and Is a Target of the Cytotoxic T-Lymphocyte Protease Granzyme A

The cytotoxic T-lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-stranded nicking is observed instead of oligonucleosomal fragmentation. A 270- to 420-kDa endoplasmic reticulum-associated complex (SET complex) containing the nucleosome assembly protein SET, the tumor suppressor pp32, and the base excision repair enzyme APE can induce single-stranded DNA damage in isolated nuclei in a granzyme A-dependent manner. The normal functions of the SET complex are unknown, but the functions of its components suggest that it is involved in activating transcription and DNA repair. We now find that the SET complex contains DNA binding and bending activities mediated by the chromatin-associated protein HMG2. HMG2 facilitates assembly of nucleoprotein higher-order structures by bending and looping DNA or by stabilizing underwound DNA. HMG2 is in the SET complex and coprecipitates with SET. By confocal microscopy, it is observed that cytoplasmic HMG2 colocalizes with SET in association with the endoplasmic reticulum, but most nuclear HMG2 is unassociated with SET. This physical association suggests that HMG2 may facilitate the nucleosome assembly, transcriptional activation, and DNA repair functions of SET and/or APE. HMG2, like SET and APE, is a physiologically relevant granzyme A substrate in targeted cells. HMG1, however, is not a substrate. Granzyme A cleavage after Lys65 in the midst of HMG box A destroys HMG2-mediated DNA binding and bending functions. Granzyme A cleavage and functional disruption of key nuclear substrates, including HMG2, SET, APE, lamins, and histones, are likely to cripple the cellular repair response to promote cell death in this novel caspase-independent death pathway

DNA sensor cGAS-mediated immune recognition

Abstract The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs