RESUMEN

@#Abstract：Long interspersed element⁃1（LINE⁃1）is the only known active and autonomously transposable retroelement in human cells，which is related to autoimmune diseases and plays important roles in activating and regulating the antiviral innate immunity of cells，especially the level of interferon（IFN）. This paper reviews the mechanisms of several non ⁃ structural proteins from human immunodeficiency virus（HIV），hepatitis B virus（HBV）and other viruses participating in the regulation of LINE ⁃ 1 activity. These mechanisms not only ensure the normal expression of viral genome，but also participate in the cellular innate immunity regulation，the inhibition of which may provide new strategies to develop treatments of diseases caused by viruses.

RESUMEN

The activation and dysregulation of retrotransposons has been identified in the CNS of individuals with the fatal neurodegenerative disorder Amyotrophic lateral sclerosis (ALS). This includes elements from multiple different families and subfamilies of retrotransposons, however there is limited knowledge of the specific loci from which this expression occurs in ALS. The long interspersed element-1 (L1) is the only autonomous retrotransposon in the human genome and members of this family of elements maintain the ability to mobilise. Despite L1s contributing to 17% of the human genome only 80-100 L1s encode the required proteins for mobilisation and are retrotransposition competent. Identifying the specific loci from which L1 expression occurs will inform on the potential functional consequences of their expression, such as the potential for somatic retrotransposition or DNA damage caused by the endonuclease activity of the ORF2 protein of the L1. Here we characterised L1 loci expression using the L1EM tool ( https://github.com/FenyoLab/L1EM ) in RNA sequencing data from 518 samples across four tissues (motor cortex, frontal cortex, cerebellum and cervical spinal cord) in the Target ALS cohort obtained from the New York Genome Center. There was a significant reduction in total intact L1 expression (those that encode functional proteins) in two brain regions of individuals with ALS compared to controls and clustering of the ALS brain regions occurred based on their intact L1 expression profile. Although overall the levels of L1 expression were reduced in ALS/ALS with other neurological disorder (ND) there were individuals in which L1s were expressed at much higher levels than the rest of the ALS/ALSND cohort. Expressed L1 loci were more frequently located in introns compared to those not expressed and the level of L1 expression positively correlated with the expression of the gene in which it was located. Significant differences were observed in the expression profiles of L1s in ALS and specific features of these elements, such as location in the genome and whether or not they are intact, were significantly associated with those that were expressed in the cohort.

Asunto(s)

RESUMEN

The Unconventional prefoldin RPB5 interacting protein (URI), also known as RPB5-Mediating Protein (RMP) has been shown to play several regulatory roles in different cellular compartments including the mitochondria, as a phosphatase binding protein; in the cytoplasm, as a chaperone-like protein; and in the nucleus, as a transcriptional regulator through binding to RPB5 and RNA polymerase II (polII). This chapter focuses on the role URI plays in transcriptional regulation in the prostate cell. In prostate cells, URI is tightly bound to another prefoldin-like protein called UXT, a known androgen receptor (AR) cofactor. Part of a multiprotein complex, URI and UXT act as transcriptional repressors, and URI regulates KAP1 through PP2A phosphatase activity. The discovery of the interaction of URI and UXT with KAP1, AR, and PP2A, as well as the numerous interactions between URI and components of the R2TP/prefoldin-like complex, RPB5, and nuclear proteins involved in DNA damage response, chromatin remodeling and gene transcription, reveal a pleiotropic effect of the URI/UXT complex on nuclear processes. The mechanisms by which URI/UXT affect transcription, chromatin structure and regulation, and genome stability, remain to be elucidated but will be of fundamental importance considering the many processes affected by alterations of URI/UXT and other prefoldins and prefoldin-like proteins.

Asunto(s)