Pseudogene: Relevant or Irrelevant?

Abstract

With the advancement of high-throughput technologies, the pivotal role of non-coding RNA (ncRNA) as a master regulator of various biological functions has become increasingly apparent. Historically considered non-functional and labeled as "junk DNA," pseudogenes can be transcribed into RNA, indicating a potential role similar to ncRNAs. Recent research suggests that some pseudogenes can encode functional peptides or proteins. A growing body of evidence has revealed that pseudogenes and their derived functional molecules are involved in various biological processes and can serve as prognostic markers in cancers. This review comprehensively summarizes and discusses the current understanding of the functional roles of pseudogenes and their derived molecules in biological functions.

Keywords: Junk DNA; Non-coding RNA; Peptide; Prognosis; Pseudogene.

Fig. 1

Identification of Pseudogenes (A) Publication Trends: The number of pseudogene-related articles published from 1977 to 2023 is shown. (B) Processed Pseudogenes: Pseudogene-derived mRNA can be reverse transcribed into complementary DNA (cDNA) and then integrated into the host genome via a retrotransposon pathway, forming processed pseudogenes. These can be identified on different chromosomes. (C) Unprocessed Pseudogenes: During gene duplication, mutations occur within the duplicated gene, resulting in an unprocessed pseudogene. Notably, the parental gene retains normal function. (D) Unitary Pseudogenes: Multiple mutations within genes can lead to a loss of function, creating unitary pseudogenes.

Fig. 2

The Role of Pseudogenes in Cancer Progression (A) Competing Endogenous RNAs (ceRNAs): Pseudogene-derived transcripts express miRNA-interacting regions that act as competitors, sequestering miRNA function. (B) RNA-Binding Protein Interaction: Pseudogene-derived transcripts contain RNA-binding protein (RBP) binding regions, which competitively associate with RBPs, inhibiting RBP-mediated biological processes. (C) PRC2 Complex Association: Pseudogene-derived transcripts can be related to Polycomb Repressive Complex 2 (PRC2) components, such as EZH2. This complex regulates downstream gene expression via epigenetic mechanisms. M: methylation. (D) Endogenous siRNAs (esiRNAs): Pseudogene-derived transcripts exhibit unique patterns complementary to target mRNAs, forming RNA-RNA duplexes. Dicer processes these duplexes to generate endogenous siRNAs (esiRNAs), suppressing target gene expression. (E) Functional Peptides or Proteins: Pseudogene-derived transcripts possess open reading frames (ORFs) with the potential to encode functional peptides or proteins. (F) RNA Modification: RNA modification-related proteins, such as METTL3, regulate pseudogene expression in an m6A-dependent manner. Additionally, pseudogene-derived transcripts can associate with or be directly modified by RNA modification-related proteins, contributing to the modulation of cellular functions.