SLU7: A New Hub of Gene Expression Regulation-From Epigenetics to Protein Stability in Health and Disease

Abstract

SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3' splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.

Keywords: alternative splicing; cancer; cell cycle; differentiation; epigenetics; gene expression; genomic stability; liver pathophysiology; stress; transcription.

Figure 1

Schematic representation of the different mechanisms involved in regulating gene expression. The sequential regulatory events are: (1) epigenetics modifications at chromatin, (2) transcription of DNA to RNA, (3) splicing of pre-mRNA, (4) mRNA transport to cytoplasm, (5) translation of mRNA to protein, (6) protein folding and (7) protein post-translational modifications. Abbreviations: ncRNA, non-coding RNA; tRNA, transferring RNA; rRNA, ribosomal RNA; Pre-mRNA, pre-messenger RNA; mRNA, messenger RNA.

Figure 2

Schematic representation of human SLU7, depicting SLU7’s gene location on the long arm of chromosome 5 (5q33.3) and its pre-mRNA and protein structure. The pre-mRNA transcript contains 16 exons and is 3480 bp in length. The encoded protein weights approximately 68.4 kDa, and it contains four different domains: a nuclear location signal (NLS), a zinc knuckle motif, four stretches of leucine repeats and a lysine-rich domain.

Figure 3

Splicing events in normal and SLU7-knockdown cells. Examples of constitutive and aberrant splice variants in normal and SLU7-knockdown cells and their cellular consequences. Some examples are the tumor suppressor gene TAp73, the splicing factor SRSF3, the gene implicated in sister chromatid cohesion (SCC) sororin, the metabolic insulin receptor (INSR), the metabolic enzymes cytochrome P450 (CYP4F3) and D-aspartate oxidase (DDO), the deacetylase enzyme sirtuin 1 (SIRT1) and the polycistronic microRNA cluster miR17-92. Blue or green boxes represent the alternative exons or introns. Abbreviations: PTC, premature termination codon; SCC, sister chromatid cohesion; TSG, tumor suppressor gene; SRSF3-TR, truncated SRSF3.

Figure 4

Schematic representation of SLU7 participation at different levels of gene expression regulation. (A) SLU7 acts as an epigenetic modulator by participating in the DNA methylation complex and by regulating the protein stability of DNMT1. (B) SLU7 regulates transcription by interaction with transcriptional complexes (cAMP-induced complex) or by regulating the expression of transcription factors (HNF4α1). (C) SLU7, through its canonical function as a splicing factor, regulates the splicing of numerous genes, either by direct binding to different targets or by regulating the splicing and expression of other splicing factors. (D) SLU7 regulates protein stability through the control of post-translational modifications, as in the case of the acetylation of DNMT1, or by inhibiting oxidative stress-mediated protein degradation, as in the case of HNF4α1.

Figure 5

Schematic representation depicting SLU7’s involvement in the process of hepatocarcinogenesis. During the progression of liver disease, the expression of SLU7 decreases in parallel with the alteration of essential cellular functions. However, the residual SLU7 expression in tumoral cells is essential for their survival. The bottom box depicts some SLU7-controlled gene expression events that are altered during liver disease progression. Abbreviations: HCC, hepatocellular carcinoma; TAGIN, transcription-associated genome instability.

Figure 6

Schematic representation compiling the involvement of SLU7 in the regulation of gene expression at different levels and in cellular functions. See text for details. Abbreviations: ROS, reactive oxygen species; SCC, sister chromatid cohesion; TAGIN, Transcription-associated genome instability.