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RNAse MRP: trust the process(ing)

You’ve probably heard of ribonucleic acid (RNA) and proteins. But did you know that they can combine to work together in a cell? This complex is called a ribonucleoprotein, and they can have various functions. One ribonucleoprotein called RNAse MRP (mitochondrial RNA processing) is involved in modifying RNA in mitochondria and in eukaryotic cells.

Structure

    RNAse MRP is a complex of a single strand of RNA and eleven proteins (Figure 1). This RNA is a noncoding RNA, meaning that it will not be translated into a protein. The atoms that make up the amino acids of the protein interact with the atoms of the nucleic acids of the RNA in order for them to stick together (Figure 2). The substrate binding domain of RNAse MRP is located in the center of the ribonucleoprotein, and it consists of the RNA and the proteins Pop1, Pop4, Pop5, and Rpp1 (Figure 1).

Figure 1. The structure of RNAse MRP. The top 2 pictures show the front and back of RNAse MRP. The bottom 2 pictures are the same; however, they make the proteins slightly transparent to show the RNA portion more clearly. Source: Perederina et al 2020.


Figure 2. This figure illustrates the binding of protein and RNA in RNAse MRP. The blue ribbon portion represents the protein Rmp1, and the blue labels designate parts of the protein. The other structure in this figure represents the RNA, and it is color-coded according to each element on the periodic table. For example, oxygen is dark blue. The gray labels represent different nucleic acids, such as uridine (located in the 225th and 226th positions of the RNA strand). Source: Perederina et al 2020.


Function

    RNAse MRP is located in mitochondria and nuclei. Its name comes from its ability to cleave RNA primers on mitochondrial DNA during DNA replication. For a refresher on why DNA replication needs RNA primers, check out this video! It shows eukaryotic DNA replication, so the machinery used in mitochondria (which are prokaryotes and have their own genome separate from us) is slightly different, but the logic behind it is the same. 


    According to Chang and Clayton (1987), there are several reasons why RNAse MRP would be able to cleave RNA primers. For example, the RNAse could be helping degrade the primer. In order to complete DNA replication, the RNA primer has to be removed so that DNA can be filled in. Mitochondrial DNA replication can have a particularly long RNA primer, so cleaving it could speed up the process. Alternatively, RNAse MRP cleaving could be an important step in making a functional RNA primer.


    RNAse MRP has a purpose in more than just the mitochondria. In their study, Goldfarb and Cech (2017) discovered the purpose of RNAse MRP in human cells. In order to achieve this, they used CRISPR to remove the gene RMRP, which codes for the RNAse. They found that without RNAse MRP, cells would accumulate pre-rRNA (precursor rRNA). rRNA is ribosomal RNA, which is an important part of ribosomes (Figure 3). Since ribosomes are necessary to make proteins, the lack of RNAse MRP will prevent cell growth and division. Pre-rRNA needs several modifications before it can be integrated into a ribosome. RNAse MRP is responsible for the cleavage of pre-rRNA in its internal transcribed spacer 1 (ITS1) section, which separates the genes for the large and small ribosomal subunits. 

Figure 3. Large and small subunits of a ribosome. rRNA is shown in orange and yellow, while proteins are shown in purple. Source: PDB-101: Molecule of the Month: Ribosomal Subunits (rcsb.org)


Possible Therapeutic Approaches

    Mutations in RNAse MRP are implicated in several types of diseases. Cartilage-hair hypoplasia (CHH) is a rare disease that occurs most often in the Old Order Amish population and in people of Finnish descent. It results in immune deficiency, skeletal abnormalities, and a higher risk of cancer. RNAse MRP mutations also cause metaphyseal dysplasia without hypotrichosis and anauxetic dysplasia, both of which affect skeletal development. In order to treat these diseases, it is important to understand the mechanism and purpose of RNAse MRP. As Goldfarb and Cech (2017) illustrated with their experiment, it is possible to edit the RMRP gene using CRISPR technology, which could be studied as a potential new therapeutic.




References

“Cartilage Hair Hypoplasia.” Johns Hopkins Medicine, https://www.hopkinsmedicine.org/health/conditions-and-diseases/cartilage-hair-hypoplasia.

“Cartilage-Hair Hypoplasia.” MedlinePlus, U.S. National Library of Medicine, 24 Nov. 2021, https://medlineplus.gov/genetics/condition/cartilage-hair-hypoplasia/#causes.

Chang, D.D., and D.A. Clayton. “A Novel Endoribonuclease Cleaves at a Priming Site of Mouse Mitochondrial DNA Replication.” The EMBO Journal, vol. 6, no. 2, 1987, pp. 409–417., https://doi.org/10.1002/j.1460-2075.1987.tb04770.x.

Clayton, D. A. “Transcription and Replication of Mitochondrial DNA.” Human Reproduction, vol. 15, no. suppl 2, 2000, pp. 11–17., https://doi.org/10.1093/humrep/15.suppl_2.11.

Goldfarb, Katherine C., and Thomas R. Cech. “Targeted CRISPR Disruption Reveals a Role for RNase MRP RNA in Human Preribosomal RNA Processing.” Genes & Development, vol. 31, no. 1, 2017, pp. 59–71., https://doi.org/10.1101/gad.286963.116.

Martin, Allison N, and Yong Li. “RNase MRP RNA and Human Genetic Diseases.” Cell Research, vol. 17, no. 3, 2006, pp. 219–226., https://doi.org/10.1038/sj.cr.7310120.

Mattijssen, Sandy, et al. “RNase MRP and Disease.” Wiley Interdisciplinary Reviews: RNA, vol. 1, no. 1, 2010, pp. 102–116., https://doi.org/10.1002/wrna.9.

“PDB101: Molecule of the Month: Ribosomal Subunits.” RCSB, https://pdb101.rcsb.org/motm/10.

Perederina, Anna, et al. “Cryo-EM Structure of Catalytic Ribonucleoprotein Complex RNase MRP.” Nature Communications, vol. 11, no. 1, 2020, https://doi.org/10.1038/s41467-020-17308-z. 

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