THE GUARDIAN OF RIBOSOMAL BIOGENESIS: RETROTRANSPOSON R2 ORCHESTRATES RIBOSOMAL DNA COPY NUMBER MAINTENANCE ACROSS GENERATIONS
Humans are a functional super body due to 10,000 to 100,000 protein expressions in every cell, which aid in metabolism, signalling, communication, immunity, etc. However, for these countless proteins to be expressed, they need an enormous number of ribosomes (for translation) to be produced. This need for ribosomes is solved by something called ribosomal DNA (rDNA) copy number maintenance. For the rapid protein synthesis, the rDNA loci have been adapted in such a way that there is not one copy but around 300-400 tandemly repeated ribosomal RNA copies. These large copy numbers (CN) satisfy the need for the rapid production of protein in the body, which is highly needed in germ and somatic cells.
However, the repetitive nature of the rDNA puts them into danger by making them prone to intrachromatid recombination, which leads to deletion or reduction of the rDNA CN. In intrachromatid recombination, due to the similar rDNA repeats in the same chromatid, a homologous pairing is formed by which recombination happens, resulting in excision of the intervening DNA segment between the repeats. Despite this, spontaneous rDNA CN loss is countered by rDNA CN expansion.
Intrachromatid recombination due to repeat elements in the chromatid
rDNA CN expansion is mediated by unequal sister chromatid exchange (USCE), which is necessary for the lineage to continue in the metazoan germline. USCE is triggered by double-strand breaks (DSBs) in the rDNA loci, which leads to homology-dependent recombinational repair and leads to one sister chromatid acquiring more copies, i.e, when rDNA loci are replicated, a DSB is created in one copy, which is repaired by taking another copy as template. Since rDNA consists of many repeated copies, the repair system can mistakenly copy too many repeats onto the damaged strand. This leads to one chromatid gaining extra rDNA copies, which are highly studied in Drosophila melanogaster.
Role of USCE in rDNA Copy Number Variation and Cell Lineage Determination
Despite the mechanism of the USCE, scientists were not sure how this DSB is created within the rDNA and loci and how they are regulated. The answer to the question is now published in Nature Communications titled “Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance”, where they found that a retrotransposon called R2 is responsible for the DBS and this is regulated by insulin signalling.
The paper showed that rDNA copy number can be increased by R2 retrotransposon alone and by R2-induced USCE. And R2-induced USCE is highly shown in germline stem cells (GSCs), where when GSCs are divided asymmetrically, the chromatid with more rDNA copy is preferentially retained as stem cells and the other differentiates into germline progenitor cells or spermatogonia (SG). Moreover, they found that the rDNA CN expansion or magnification is only seen in GSC, and the activity of R2 is only expressed when there is low rDNA CN.
Regulation of rDNA Copy Number through R2 Activity and USCE
Through single-cell RNA sequencing in bobbed male (with low rDNA CN) and normal male Drosophila melanogaster, they found that insulin-like growth Receptor (InR) was downregulated in GSCs with low rDNA CN. They found that when there is a low rDNA CN, InR is downregulated, which results in R2 expression and rDNA CN magnification. Moreover, mTORC1, a downstream effector of Insulin/Insulin-like Growth Factor Signaling (IIS), is involved in the suppression of R2. Mechanistically, when rDNA CN is abundant, mTORC1 expression is higher, which suppresses the R2; however, when the CN is low, mTORC1 is repressed and R2 is expressed, which leads to USCE and an increase in the rDNA copy number.
As IIS and mTor are mediators of nutrient signalling, the authors explored how dietary conditions influence the germline R2 expression and rDNA amplification activity. They found that in low low-calorie diet, enhanced R2 expression is seen, and in a high-calorie diet, R2 expression is suppressed. When Normal rDNA containing males were fed with low low-calorie diet, and when low rDNA containing males were fed with a normal diet, downregulation of mTORC1 and IIS was seen with high expression of R2. This evidence suggested that dietary condition is functionally linked to rDNA CN.
Role of dietary condition in germline R2 expression and rDNA amplification activity
Interestingly, the authors found that mTORC1 is a positive regulator of rDNA transcription; however, in the case of R2 expression, they are negative regulators. The authors propose that mTORC1 may differentially regulate R2-inserted and uninserted rDNA copies. However, the potential of the paper doesn't end there. The authors still pay future direction to find how the ribosome biogenesis is sensed by the mTORC or IIS pathway, and how they are linked to the nutrients, which is still unknown, and something that can be explored further.
REFERENCE
Nelson, J.O., Slicko, A., Raz, A.A. et al. Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance. Nat Commun 16, 399 (2025). https://doi.org/10.1038/s41467-024-55725-6
IMAGE CREDITS
ResearchGate, https://images.app.goo.gl/71KVCQsoNJSMsmUm7
Cell Press, https://images.app.goo.gl/HS7auTGUidVnvQK47
Nature Communications, https://images.app.goo.gl/MexpppbEg3x5m3Hs5
Nature Communications, https://images.app.goo.gl/qU5WSThyZj5rXp4G9
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