# RRM2B

## Overview
RRM2B is a gene that encodes the ribonucleotide reductase regulatory TP53 inducible subunit M2B, also known as p53R2, a crucial component of the ribonucleotide reductase enzyme complex. This protein plays a significant role in DNA repair and synthesis by converting ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA replication and repair processes. RRM2B is particularly important under conditions of cellular stress, such as DNA damage or oxidative stress, where it helps maintain genomic stability and mitochondrial DNA integrity (Liu2005The; Kuo2016PYCR1). The protein is involved in interactions with other proteins, such as RRM1, PYCR1, and PYCR2, which are critical for its function in antioxidation and cellular defense mechanisms (Kuo2016PYCR1). Mutations in the RRM2B gene are linked to mitochondrial DNA depletion syndromes and other mitochondrial disorders, highlighting its clinical significance (Wang2024Case; Kollberg2009A). Additionally, RRM2B has been implicated in cancer, where its amplification is associated with tumor progression and therapeutic responses (Iqbal2021RRM2B).

## Structure
The RRM2B protein, also known as p53R2, is a subunit of ribonucleotide reductase involved in DNA repair. Its primary structure shares over 80% sequence identity with hRRM2, another small RNR subunit, and shows 90% identity to the mouse p53R2 protein (Guittet2001Mammalian; Smith20092.6). A notable difference in the primary structure is the absence of 33 amino acid residues in the N terminus compared to the R2 protein (Guittet2001Mammalian).

The secondary structure of hp53R2 includes helices and loops forming a central bundle, with iron-binding sites created by α-helices B, C, E, and F (Smith20092.6). The tertiary structure reveals a natural dimer per asymmetric unit, with differences in iron coordination between monomers A and B (Smith20092.6). The quaternary structure involves the formation of an active ribonucleotide reductase complex with the R1 protein (Guittet2001Mammalian).

The protein contains conserved iron ligands and a tyrosyl free radical, essential for its function (Guittet2001Mammalian). Structural differences, such as the presence of a tyrosine (Y164) instead of a cysteine, create an open channel linked to its increased susceptibility to iron chelators (Smith20092.6). These structural features are crucial for understanding the distinct biological roles and regulatory mechanisms of RRM2B.

## Function
RRM2B encodes a subunit of ribonucleotide reductase, which is essential for the conversion of ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates (dNDPs), a critical step in DNA synthesis and repair. This process is vital for maintaining the deoxyribonucleotide triphosphate (dNTP) pool necessary for DNA replication and repair, particularly under stress conditions such as DNA damage or oxidative stress (Liu2005The; Kuo2016PYCR1). RRM2B is involved in the G1/S-phase transition of the cell cycle, where it translocates from the cytoplasm to the nucleus to facilitate DNA replication by providing dNTPs (Liu2005The).

In addition to its role in nuclear DNA synthesis, RRM2B is crucial for mitochondrial DNA maintenance. It helps protect cells from oxidative stress by reducing reactive oxygen species (ROS) levels and maintaining mitochondrial membrane potential. This antioxidative function is partly mediated through interactions with PYCR1 and PYCR2, which are involved in proline metabolism and antioxidation (Kuo2016PYCR1). RRM2B's activity in both the cytoplasm and mitochondria underscores its importance in cellular defense mechanisms and genomic stability (Cho2015RRM2B‐Mediated).

## Clinical Significance
Mutations in the RRM2B gene are associated with several severe mitochondrial disorders, primarily mitochondrial DNA depletion syndromes (MDDS). These conditions are characterized by a significant reduction in mitochondrial DNA (mtDNA) copy number, leading to symptoms such as hypotonia, lactic acidosis, and failure to thrive, often resulting in early death in infancy (Wang2024Case; Kollberg2009A). The RRM2B gene encodes the p53R2 protein, which is crucial for maintaining the mitochondrial deoxyribonucleotide triphosphate (dNTP) pool necessary for mtDNA replication. Variants in RRM2B can lead to an imbalanced dNTP pool, causing mtDNA depletion and MDDS (Wang2024Case).

RRM2B mutations also contribute to progressive external ophthalmoplegia (PEO), a condition characterized by muscle weakness and multiple mtDNA deletions (Pitceathly2012Adults). The clinical severity of these conditions often correlates with the specific genotype and the location of the mutation within the gene (Wang2024Case).

In cancer, RRM2B amplifications have been observed in various tumor types, including breast and lung cancers, and are associated with distinct tumor mutation signatures. These amplifications may influence tumor progression and response to therapy (Iqbal2021RRM2B).

## Interactions
RRM2B, also known as p53R2, is involved in several protein interactions that are crucial for its function in DNA repair and oxidative stress response. RRM2B interacts with RRM1 to form a ribonucleotide reductase complex essential for deoxyribonucleotide production, which is vital for DNA synthesis and repair (Specks2015A; Kuo2016PYCR1). The interaction with RRM1 is influenced by the presence of a Flag tag at the C-terminus of RRM2B, which can reduce the co-immunoprecipitation of RRM1, suggesting that the tagging position can affect these interactions (Kuo2016PYCR1).

RRM2B also interacts with PYCR1 and PYCR2, proteins involved in proline synthesis and antioxidation activity. These interactions were identified through mass spectrometry and validated by immunoprecipitation and Western blotting, indicating that RRM2B can pull down PYCR1 and PYCR2, although the reverse interaction is less efficient (Kuo2016PYCR1). PYCR1 and PYCR2 are found to co-immunoprecipitate with each other, suggesting they may form a complex with RRM2B in vivo (Kuo2016PYCR1). These interactions are implicated in the collaborative role of RRM2B, PYCR1, and PYCR2 in protecting cells from oxidative stress (Kuo2016PYCR1).


## References


[1. (Pitceathly2012Adults) Robert D. S. Pitceathly, Conrad Smith, Carl Fratter, Charlotte L. Alston, Langping He, Kate Craig, Emma L. Blakely, Julie C. Evans, John Taylor, Zarfishan Shabbir, Marcus Deschauer, Ute Pohl, Mark E. Roberts, Matthew C. Jackson, Christopher A. Halfpenny, Peter D. Turnpenny, Peter W. Lunt, Michael G. Hanna, Andrew M. Schaefer, Robert McFarland, Rita Horvath, Patrick F. Chinnery, Douglass M. Turnbull, Joanna Poulton, Robert W. Taylor, and Gráinne S. Gorman. Adults with rrm2b-related mitochondrial disease have distinct clinical and molecular characteristics. Brain, 135(11):3392–3403, October 2012. URL: http://dx.doi.org/10.1093/brain/aws231, doi:10.1093/brain/aws231. This article has 66 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/brain/aws231)

[2. (Guittet2001Mammalian) Olivier Guittet, Pelle Håkansson, Nina Voevodskaya, Susan Fridd, Astrid Gräslund, Hirofumi Arakawa, Yusuke Nakamura, and Lars Thelander. Mammalian p53r2 protein forms an active ribonucleotide reductasein vitro with the r1 protein, which is expressed both in resting cells in response to dna damage and in proliferating cells. Journal of Biological Chemistry, 276(44):40647–40651, November 2001. URL: http://dx.doi.org/10.1074/jbc.m106088200, doi:10.1074/jbc.m106088200. This article has 145 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m106088200)

[3. (Liu2005The) Xiyong Liu, Bingsen Zhou, Lijun Xue, Jennifer Shih, Karen Tye, Christina Qi, and Yun Yen. The ribonucleotide reductase subunit m2b subcellular localization and functional importance for dna replication in physiological growth of kb cells. Biochemical Pharmacology, 70(9):1288–1297, November 2005. URL: http://dx.doi.org/10.1016/j.bcp.2005.08.005, doi:10.1016/j.bcp.2005.08.005. This article has 26 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.bcp.2005.08.005)

[4. (Smith20092.6) Peter Smith, Bingsen Zhou, Nam Ho, Yate-Ching Yuan, Leila Su, Shiou-Chuan Tsai, and Yun Yen. 2.6 å x-ray crystal structure of human p53r2, a p53-inducible ribonucleotide reductase,. Biochemistry, 48(46):11134–11141, October 2009. URL: http://dx.doi.org/10.1021/bi9001425, doi:10.1021/bi9001425. This article has 32 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi9001425)

[5. (Specks2015A) Julia Specks, Emilio Lecona, Andrés J. Lopez-Contreras, and Oscar Fernandez-Capetillo. A single conserved residue mediates binding of the ribonucleotide reductase catalytic subunit rrm1 to rrm2 and is essential for mouse development. Molecular and Cellular Biology, 35(17):2910–2917, September 2015. URL: http://dx.doi.org/10.1128/mcb.00475-15, doi:10.1128/mcb.00475-15. This article has 8 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.00475-15)

[6. (Iqbal2021RRM2B) Waleed Iqbal, Elena V. Demidova, Samantha Serrao, Taha ValizadehAslani, Gail Rosen, and Sanjeevani Arora. Rrm2b is frequently amplified across multiple tumor types: implications for dna repair, cellular survival, and cancer therapy. Frontiers in Genetics, March 2021. URL: http://dx.doi.org/10.3389/fgene.2021.628758, doi:10.3389/fgene.2021.628758. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fgene.2021.628758)

[7. (Kuo2016PYCR1) Mei-Ling Kuo, Mabel Bin-Er Lee, Michelle Tang, Willem den Besten, Shuya Hu, Michael J. Sweredoski, Sonja Hess, Chih-Ming Chou, Chun A. Changou, Mingming Su, Wei Jia, Leila Su, and Yun Yen. Pycr1 and pycr2 interact and collaborate with rrm2b to protect cells from overt oxidative stress. Scientific Reports, January 2016. URL: http://dx.doi.org/10.1038/srep18846, doi:10.1038/srep18846. This article has 58 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/srep18846)

[8. (Wang2024Case) Yanjun Wang, Ling Hang, Weihua Shou, Cuifen Li, Fangling Dong, Xingxing Feng, Ruohong Jin, Bin Li, and Shufang Xiao. Case report: a novel rrm2b variant in a chinese infant with mitochondrial dna depletion syndrome and collective analyses of rrm2b variants for disease etiology. Frontiers in Pediatrics, April 2024. URL: http://dx.doi.org/10.3389/fped.2024.1363728, doi:10.3389/fped.2024.1363728. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fped.2024.1363728)

[9. (Kollberg2009A) Gittan Kollberg, Niklas Darin, Karin Benan, Ali-Reza Moslemi, Sigurd Lindal, Már Tulinius, Anders Oldfors, and Elisabeth Holme. A novel homozygous rrm2b missense mutation in association with severe mtdna depletion. Neuromuscular Disorders, 19(2):147–150, February 2009. URL: http://dx.doi.org/10.1016/j.nmd.2008.11.014, doi:10.1016/j.nmd.2008.11.014. This article has 53 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.nmd.2008.11.014)

[10. (Cho2015RRM2B‐Mediated) Er-Chieh Cho, Mei-Ling Kuo, Jia-hui Cheng, Yu-Chi Cheng, Yi-Chen Hsieh, Yun-Ru Liu, Rong-Hong Hsieh, and Yun Yen. Rrm2b‐mediated regulation of mitochondrial activity and inflammation under oxidative stress. Mediators of Inflammation, January 2015. URL: http://dx.doi.org/10.1155/2015/287345, doi:10.1155/2015/287345. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1155/2015/287345)