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Review
. 2022 Sep 16;13(9):1659.
doi: 10.3390/genes13091659.

SR Splicing Factors Promote Cancer via Multiple Regulatory Mechanisms

Ledong Wan  1   2 , Min Deng  3 , Honghe Zhang  1
Affiliations
Review

SR Splicing Factors Promote Cancer via Multiple Regulatory Mechanisms

Ledong Wan et al. Genes (Basel). .

Abstract

Substantial emerging evidence supports that dysregulated RNA metabolism is associated with tumor initiation and development. Serine/Arginine-Rich proteins (SR) are a number of ultraconserved and structurally related proteins that contain a characteristic RS domain rich in arginine and serine residues. SR proteins perform a critical role in spliceosome assembling and conformational transformation, contributing to precise alternative RNA splicing. Moreover, SR proteins have been reported to participate in multiple other RNA-processing-related mechanisms than RNA splicing, such as genome stability, RNA export, and translation. The dysregulation of SR proteins has been reported to contribute to tumorigenesis through multiple mechanisms. Here we reviewed the different biological roles of SR proteins and strategies for functional rectification of SR proteins that may serve as potential therapeutic approaches for cancer.

Keywords: RNA processing; SR proteins; cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the 12 human SR proteins. SR proteins are presented as SRSFs with aliases indicated in the parenthesis. Shuttling SR proteins (red letters) are reported to shuttle between nucleus and cytoplasm, whereas the others (black letters) have no shuttling activity. Phosphorylation of RS domain of SRSF1 by SRPK and CLK kinases is indicated as a representative at the top.
Figure 2
Figure 2
The role of SR proteins in spliceosome assembly. Many studies have identified SR proteins involved in nearly every step of the spliceosome assembly. Firstly, SR proteins could promote the formation of E complex and its binding to the 5’-splice site to facilitate base pairing between U1 snRNA with the splice site. Next, SR proteins recruit U2 snRNA to the branch point region of pre-mRNA to form complex A. Then SR proteins form a bridging complex across two splice sites via binding to U2AF at the 3′-splice site and U1 70K at the 5′-splice site, facilitating the recruitment of U4/U6 and U5 tri snRNP complex to form complex B.
Figure 3
Figure 3
SR proteins in transcriptional elongation and genome stabilization. Through binding to nascent RNA, SR proteins hinder the R-loop formation and dynamically bridge P-TEFb to Pol II, which further catalyzes Pol II phosphorylation in its C-terminal repeat domain (CTD), promoting transcriptional elongation in many genes.
Figure 4
Figure 4
Regulation of SR proteins and their roles in mRNA export, translation, and decay. (A) SR proteins require phosphorylation to mediate spliceosome complex formation. With further dephosphorylation, SR proteins bind and export the mature mRNA into the cytoplasm. (B) SR proteins perform a significant role in NMD, which can alter NMD from taking place after mRNA export to the cytoplasm to coming up before mRNA release from the nucleus. (C) SR protein-bound mRNAs recruit the mTOR kinase resulting in the phosphorylation and release of 4E-BP, leading to enhanced translation initiation. SR proteins can enhance the mTOR kinase phosphorylating S6K1, which promotes translation initiation. Meanwhile, The SF2/ASF-dependent alternative splicing leads to Mnk2b isoform, which can activate translation. (D) Phosphorylated by kinase, such as SRPK1 or/and Clk, SR proteins are specifically recognized and transported into the nucleus by Transportin-SR protein.
Figure 5
Figure 5
Co-regulation of SR proteins on common target through multiple mechanisms. As a contributor to angiogenesis, dysregulation of VEGF splicing contributes to cancer progression and is highly correlated with acquired drug resistance. For example, upregulated expression of SRSF2 or SRSF6, as a result of transcription increased or copy number amplified, is responsible for splicing in favor of VEGF165b, which is antagonistic to tumor neovascularization in vivo. However, overactivity of SRPK1 in the tumor could phosphorylate SRSF1 and stimulate its nuclear import, which favors the selection of the proximal splice site of VEGF pre-mRNA and promotes neovascularization.
Figure 6
Figure 6
Strategies for correcting SR-protein-mediated aberrant alternative splicing. (A) Elevated SR proteins alter RNA splicing. (B–D) Principles for targeting SR proteins induced aberrant RNA splicing in cancer. (B) Antisense oligonucleotides bind to RNA and block SR proteins’ effect on target RNA alternative splicing. (C) Small molecular inhibitors bind to RRM domain of SR proteins and inhibit RNA binding. Stars represent small molecular inhibitors. (D) Decoy oligonucleotides composed of SR protein binding sequence bind to SR proteins and block their access to the target RNA.
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Grants and funding

This work is supported by the Natural Science Foundation of Zhejiang Province (LZ21H160001), CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-044), Medical Health Scientific Research Fund of Zhejiang Province (2020PY022), and Agricultural and Social Development Scientific Research Fund of Hangzhou (20191231Y200).