Regulation of SUMOylation on RNA metabolism in cancers

Abstract

Post-translational modifications of proteins play very important roles in regulating RNA metabolism and affect many biological pathways. Here we mainly summarize the crucial functions of small ubiquitin-like modifier (SUMO) modification in RNA metabolism including transcription, splicing, tailing, stability and modification, as well as its impact on the biogenesis and function of microRNA (miRNA) in particular. This review also highlights the current knowledge about SUMOylation regulation in RNA metabolism involved in many cellular processes such as cell proliferation and apoptosis, which is closely related to tumorigenesis and cancer progression.

Keywords: RNA editing; cancer; mRNA processing; mRNA transcription; miRNA biogenesis; sumoylation.

FIGURE 1

The SUMOylation system. (A) SUMO is encoded as an inactive precursor that is cleaved by members of the SENP family to expose the C-terminal diglycine motif (1). This mature form of SUMO is then activated by forming an ATP-dependent thioesler bond with the active site of the Et enzyme (a heterodimer of SAE1 and SAE2) (2). The activated SUMO is then delivered to the active site cysteine of the E2-conjugating enzyme Ubc9. Which then catalyzes the transfer of SUMO to the target protein, either alone or with the help of a SUMO E3 ligase (3, 4). SUMOylated sub-strates show phenotypic differences from the unmodified form. DeSUMOylation is mediated by the SENP protease family (5). This process releases unmodified target protein (not shown) and mature SUMO. which can then be used for further binding to the target protein. (B) SUMO modifications most commonly target proteins with the consensus motif w-K-X-FJD. to is a hydrophobic amino acid. K is the target Lys. X is any amino acid, and DIE is Asp or Glu. SUM01 modifies substrates into monomers. While SUMO2/315 modifies substrates in poly•SUMO chains. (C) Proteins contain-ing SIMs mediate non-covalent interactions with SUMO.

FIGURE 2

Models for the functions of SUMOylation in RNA transcription and processing. (A) SUMOylation leads to transcnptional repression. Histone SUMOylation mediates transcriptional repression through recruitment of HDAC1 and HP1 (1). SUMOylation of p300 and CBP recruits HDAC6 and DAXX/HDAC2 respechvehi, leading to SUMO-dependent transcnptional repression. SUMOylation of liADC1/2/4 promotes the deacetylase activity to repress transcription (2). The SIM domain of DAXX provides a molecular explanation for the interaction between DAXX and SUMO-mod-ified transcription factors, resulting In transcriptional repression (3) SUMOylation of SAFE enhances its binding with RNAPII, thereby promoting gene transoiption (4). SUMO and MYC antagonistically control global gene expression through regulating COK9 SUMOylation. P-TEFb formation and tran-scriptional elongation. SUMOylation of CDK9 blocks its interaction with Cyclin Ti. Thereby inhibiting the formation of active P-TEFb complex (5). NELF and OSIF bind to the potymerase in a manner that restricts Pol II mobility and impairs further RNA elongation. SUMOylation regulates the recruitment of NELF to promoters upon stress to drive transcriptional downregulabon (6). SUMOytabon of PAF1/PD2 facilitates its interaction with PML proteins (7). (B) SRSF1. Bound to the exonic splicing enhancer (ESE). Interacts with Ubc9 to regulate the SUMOylation of spliceosome protein components. Thuieby increasing splicing efficiency. PRP3 acts as a component of the 114/U6 cli-snRNP. and Its SUMOylatlon Promotes U41U6/1.15 tri-snRNP formation to effect splicing. (C) SUMOylation of CPSF. PAP and Sim-pleton affects the assembly and activity of pre-mRNA 3’complex.

FIGURE 3

The effects of SUMOylation on RNA modification and RNA editing. (A) The N6-methylad-enosine writer METTL3. Reader YTHDF2 and eraser ALKBHS can be modified by SUMO. SUMOyIa-lion of METTL3 does not affect its stability. Subcellular localization. Or Interaction with MET11141 W-TAP. but significantly inhibits METTL3 m6A methyltransferase activity. YTHDF2 can be modified by SUMO1 under hypoxia. Enhancing its binding affinity to m6A-RNAs. Resulting in dysregulation of gene expression. ALKBHS SUMOylation loads to inhibition of ALKBHS m6A demethylase activity. Thereby increasing global mRNA m6A levels. (B) SUMOylation stabilizes m5C writer NSUN2 and mediates its transport into the nucleus. (C) The RNA editing enzyme ADAR1. Which converts ade-nosine to inosine, can be SUMOylated thereby inhibiting its RNA editing activity.

FIGURE 4

The effect of SUMO modification on the miRNA pathway. (A) OGCR8 SUMOyfation increases its protein stability by preventing the degradation via the ubiquitin proteasome pathway. The SUMOylation also enhances its affinity with pri-miRNA thus positively promoting the pri-miRNA direct recognition and repression of the targeted mRNA. SUMOylated KHSRP inhioits interaction with Dro-sha/DGCR8 and pri-miRNAs complex, sequentially downregulatlng a subset of miRNAS biogenesis. (B) SUMOylation of TARBP2 controls the efficiency of RNA-induced gene silencing by increasing its interaction with AGO2 and precursor miRNAs/siRNAs (C) SUMOytation enhances AGO2 turnover and antagonizes its stability. (D) SUMOylated of LIN28 A increases the binding affinity of LIN28 A and pre-let-7. Thereby leading to the degradation of pre•let-7 and reducing mature let-7 biogenesis. The intense interaction between LIN28 A and pre-let-7 can efficiently recruit TUT4 to urictylate pre-let-7 and block the processing of pre-let-7.