# RAD50

## Overview
The RAD50 gene encodes the RAD50 double strand break repair protein, a critical component of the MRN complex, which also includes MRE11 and NBS1. This protein plays a pivotal role in the repair of DNA double-strand breaks (DSBs), a crucial process for maintaining genomic stability. RAD50 is characterized as an ATPase, with its activity being essential for the conformational changes required during DNA repair. The protein's structure includes coiled-coil domains and a zinc hook motif, which are vital for DNA tethering and dimerization, respectively. These structural features enable RAD50 to facilitate both homologous recombination repair (HRR) and non-homologous end joining (NHEJ), the two primary pathways for DSB repair (Deshpande2014ATPdriven; Lafrance-Vanasse2015Envisioning). Mutations in the RAD50 gene have been linked to various genetic disorders and an increased risk of cancer, highlighting its significance in genomic maintenance and its potential as a therapeutic target (Waltes2009Human; Heikkinen2005RAD50).

## Structure
The RAD50 protein is a crucial component of the MRN complex, involved in DNA double-strand break repair. Its primary structure includes conserved motifs such as the Walker A and B motifs, which are essential for its ATPase activity (Rojowska2014Structure). The secondary structure of RAD50 features coiled-coil domains that are long and extended, allowing for the bridging of DNA molecules. These coiled-coils fold back in an antiparallel manner, bringing the ATPase domains together with the hook domain at the distal apex (Hohl2011The).

The tertiary structure of RAD50 involves ATP binding and hydrolysis, which induces conformational changes necessary for its function in DNA repair. The ATP-bound state of RAD50 facilitates the dimerization of its nucleotide-binding domains, forming a molecular clamp essential for DNA double-strand break repair (Lammens2011The). The quaternary structure of RAD50 includes its interaction with Mre11 and Nbs1 within the MRN complex, forming a heterotetrameric assembly that is crucial for DNA binding and nuclease activities (Hopfner2000Structural).

RAD50 also features a zinc hook motif, which is important for dimerization and the structural integrity of the MRN complex (Hohl2011The). Common post-translational modifications of RAD50 include phosphorylation, which may regulate its activity and interactions.

## Function
The RAD50 protein is a crucial component of the MRN complex, which also includes MRE11 and NBS1, and plays a significant role in the repair of DNA double-strand breaks (DSBs) in human cells. RAD50 is involved in both homologous recombination repair (HRR) and non-homologous end joining (NHEJ), two primary pathways for DSB repair (Rojowska2014Structure; Lafrance-Vanasse2015Envisioning). The protein's ATPase activity is essential for its function, as it undergoes ATP-driven conformational changes that regulate DNA binding and processing (Deshpande2014ATPdriven). 

RAD50's coiled-coil domains and zinc-hook structure are critical for tethering DNA ends, facilitating the bridging of DNA molecules during repair (Syed2018The; Lafrance-Vanasse2015Envisioning). These structural features enable RAD50 to maintain genomic stability by preventing incorrect end use during end joining and promoting end resection for repair processes involving microhomology (Gunn2011Correct). The MRN complex, with RAD50 as a key component, also activates ATM kinase, a crucial step in the DNA damage response, by undergoing ATP-dependent conformational changes (Lee2013Ataxia). RAD50 is primarily active in the nucleus, where it helps prevent genomic instability and cancer development (Kinoshita2009RAD50).

## Clinical Significance
Mutations in the RAD50 gene are associated with several diseases and conditions due to their role in genomic instability. The RAD50 687delT mutation is a Finnish founder mutation linked to an increased risk of breast cancer, particularly in women without a family history of the disease. This mutation is considered a low-penetrance susceptibility allele, suggesting that it may increase cancer risk when combined with other genetic and environmental factors (Heikkinen2005RAD50). 

RAD50 mutations are also implicated in a disorder resembling Nijmegen Breakage Syndrome (NBS), characterized by chromosomal instability and hypersensitivity to ionizing radiation. This condition, known as Nijmegen Breakage Syndrome-like disorder (NBSLD), shares features with NBS but lacks severe immunodeficiency and malignancies (Waltes2009Human). 

In breast cancer patients who are negative for BRCA1/2 mutations, RAD50 germline mutations are associated with poor survival outcomes, including higher risks of recurrence and disease-specific mortality (Fan2018RAD50). These findings highlight the clinical significance of RAD50 mutations in cancer predisposition and progression, underscoring the importance of RAD50 in maintaining genomic stability and its potential as a target for therapeutic interventions.

## Interactions
The RAD50 protein is a key component of the MRN complex, which includes MRE11 and NBS1, and is essential for DNA double-strand break repair. RAD50 physically interacts with MRE11 to form a stable complex, which is crucial for recombinational DNA repair. This interaction is strong enough to withstand high salt concentrations, indicating a robust association (Dolganov1996Human). The MRN complex is involved in DNA damage-induced cell-cycle checkpoints and interacts with ATM kinase to initiate DNA damage response signaling (Moncalian2004The; Lafrance-Vanasse2015Envisioning).

RAD50's interaction with DNA is ATP-dependent, with ATP binding facilitating the formation of RAD50 multimeric complexes. These complexes are involved in DNA tethering, although RAD50 alone does not form tethering complexes without the presence of other MRN components (Kinoshita2015Human). The coiled-coil domain of RAD50 is essential for connecting catalytic domains and enhancing DNA end tethering, which is critical for its function in DNA repair pathways (Deshpande2014ATPdriven).

The zinc-hook motif of RAD50 plays a significant role in dimerization, which is necessary for its function in DNA repair. This motif allows RAD50 to form intermolecular complexes that tether DNA strands, highlighting its role in maintaining genome stability (Tatebe2020Rad50).


## References


[1. (Lee2013Ataxia) Ji-Hoon Lee, Michael R. Mand, Rajashree A. Deshpande, Eri Kinoshita, Soo-Hyun Yang, Claire Wyman, and Tanya T. Paull. Ataxia telangiectasia-mutated (atm) kinase activity is regulated by atp-driven conformational changes in the mre11/rad50/nbs1 (mrn) complex. Journal of Biological Chemistry, 288(18):12840–12851, May 2013. URL: http://dx.doi.org/10.1074/jbc.m113.460378, doi:10.1074/jbc.m113.460378. This article has 0 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m113.460378)

[2. (Waltes2009Human) Regina Waltes, Reinhard Kalb, Magtouf Gatei, Amanda W. Kijas, Markus Stumm, Alexandra Sobeck, Britta Wieland, Raymonda Varon, Yaniv Lerenthal, Martin F. Lavin, Detlev Schindler, and Thilo Dörk. Human rad50 deficiency in a nijmegen breakage syndrome-like disorder. The American Journal of Human Genetics, 84(5):605–616, May 2009. URL: http://dx.doi.org/10.1016/j.ajhg.2009.04.010, doi:10.1016/j.ajhg.2009.04.010. This article has 200 citations.](https://doi.org/10.1016/j.ajhg.2009.04.010)

[3. (Heikkinen2005RAD50) K. Heikkinen. Rad50 and nbs1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis, 27(8):1593–1599, December 2005. URL: http://dx.doi.org/10.1093/carcin/bgi360, doi:10.1093/carcin/bgi360. This article has 163 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/carcin/bgi360)

[4. (Syed2018The) Aleem Syed and John A. Tainer. The mre11–rad50–nbs1 complex conducts the orchestration of damage signaling and outcomes to stress in dna replication and repair. Annual Review of Biochemistry, 87(1):263–294, June 2018. URL: http://dx.doi.org/10.1146/annurev-biochem-062917-012415, doi:10.1146/annurev-biochem-062917-012415. This article has 387 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1146/annurev-biochem-062917-012415)

[5. (Moncalian2004The) Gabriel Moncalian, Bettina Lengsfeld, Venugopal Bhaskara, Karl-Peter Hopfner, Annette Karcher, Erinn Alden, John A. Tainer, and Tanya T. Paull. The rad50 signature motif: essential to atp binding and biological function. Journal of Molecular Biology, 335(4):937–951, January 2004. URL: http://dx.doi.org/10.1016/j.jmb.2003.11.026, doi:10.1016/j.jmb.2003.11.026. This article has 78 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2003.11.026)

[6. (Rojowska2014Structure) Anna Rojowska, Katja Lammens, Florian U Seifert, Carolin Direnberger, Heidi Feldmann, and Karl‐Peter Hopfner. Structure of the rad50 <scp>dna</scp> double‐strand break repair protein in complex with <scp>dna</scp>. The EMBO Journal, 33(23):2847–2859, October 2014. URL: http://dx.doi.org/10.15252/embj.201488889, doi:10.15252/embj.201488889. This article has 54 citations.](https://doi.org/10.15252/embj.201488889)

[7. (Deshpande2014ATPdriven) R. A. Deshpande, G. J. Williams, O. Limbo, R. S. Williams, J. Kuhnlein, J.-H. Lee, S. Classen, G. Guenther, P. Russell, J. A. Tainer, and T. T. Paull. Atp-driven rad50 conformations regulate dna tethering, end resection, and atm checkpoint signaling. The EMBO Journal, 33(5):482–500, February 2014. URL: http://dx.doi.org/10.1002/embj.201386100, doi:10.1002/embj.201386100. This article has 124 citations.](https://doi.org/10.1002/embj.201386100)

[8. (Fan2018RAD50) Cong Fan, Juan Zhang, Tao Ouyang, Jinfeng Li, Tianfeng Wang, Zhaoqing Fan, Tie Fan, Benyao Lin, and Yuntao Xie. Rad50 germline mutations are associated with poor survival in brca1/2–negative breast cancer patients. International Journal of Cancer, 143(8):1935–1942, July 2018. URL: http://dx.doi.org/10.1002/ijc.31579, doi:10.1002/ijc.31579. This article has 25 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/ijc.31579)

[9. (Kinoshita2015Human) Eri Kinoshita, Sari van Rossum-Fikkert, Humberto Sanchez, Aryandi Kertokalio, and Claire Wyman. Human rad50 makes a functional dna-binding complex. Biochimie, 113:47–53, June 2015. URL: http://dx.doi.org/10.1016/j.biochi.2015.03.017, doi:10.1016/j.biochi.2015.03.017. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.biochi.2015.03.017)

[10. (Hopfner2000Structural) Karl-Peter Hopfner, Annette Karcher, David S. Shin, Lisa Craig, L.Matthew Arthur, James P. Carney, and John A. Tainer. Structural biology of rad50 atpase. Cell, 101(7):789–800, June 2000. URL: http://dx.doi.org/10.1016/S0092-8674(00)80890-9, doi:10.1016/s0092-8674(00)80890-9. This article has 1197 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/S0092-8674(00)80890-9)

[11. (Gunn2011Correct) Amanda Gunn, Nicole Bennardo, Anita Cheng, and Jeremy M. Stark. Correct end use during end joining of multiple chromosomal double strand breaks is influenced by repair protein rad50, dna-dependent protein kinase dna-pkcs, and transcription context. Journal of Biological Chemistry, 286(49):42470–42482, December 2011. URL: http://dx.doi.org/10.1074/jbc.M111.309252, doi:10.1074/jbc.m111.309252. This article has 125 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M111.309252)

[12. (Dolganov1996Human) Gregory M. Dolganov, Richard S. Maser, Alexander Novikov, Liana Tosto, Susan Chong, Debra A. Bressan, and John H. J. Petrini. Human rad50 is physically associated with human mre11: identification of a conserved multiprotein complex implicated in recombinational dna repair. Molecular and Cellular Biology, 16(9):4832–4841, September 1996. URL: http://dx.doi.org/10.1128/MCB.16.9.4832, doi:10.1128/mcb.16.9.4832. This article has 320 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.16.9.4832)

[13. (Tatebe2020Rad50) Hisashi Tatebe, Chew Theng Lim, Hiroki Konno, Kazuhiro Shiozaki, Akira Shinohara, Takayuki Uchihashi, and Asako Furukohri. Rad50 zinc hook functions as a constitutive dimerization module interchangeable with smc hinge. Nature Communications, January 2020. URL: http://dx.doi.org/10.1038/s41467-019-14025-0, doi:10.1038/s41467-019-14025-0. This article has 25 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-019-14025-0)

[14. (Lammens2011The) Katja Lammens, Derk J. Bemeleit, Carolin Möckel, Emanuel Clausing, Alexandra Schele, Sophia Hartung, Christian B. Schiller, Maria Lucas, Christof Angermüller, Johannes Söding, Katja Sträßer, and Karl-Peter Hopfner. The mre11:rad50 structure shows an atp-dependent molecular clamp in dna double-strand break repair. Cell, 145(1):54–66, April 2011. URL: http://dx.doi.org/10.1016/j.cell.2011.02.038, doi:10.1016/j.cell.2011.02.038. This article has 168 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.cell.2011.02.038)

[15. (Kinoshita2009RAD50) Eri Kinoshita, Eddy van der Linden, Humberto Sanchez, and Claire Wyman. Rad50, an smc family member with multiple roles in dna break repair: how does atp affect function? Chromosome Research, 17(2):277–288, February 2009. URL: http://dx.doi.org/10.1007/s10577-008-9018-6, doi:10.1007/s10577-008-9018-6. This article has 51 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s10577-008-9018-6)

[16. (Hohl2011The) Marcel Hohl, Youngho Kwon, Sandra Muñoz Galván, Xiaoyu Xue, Cristina Tous, Andrés Aguilera, Patrick Sung, and John H J Petrini. The rad50 coiled-coil domain is indispensable for mre11 complex functions. Nature Structural &amp; Molecular Biology, 18(10):1124–1131, September 2011. URL: http://dx.doi.org/10.1038/nsmb.2116, doi:10.1038/nsmb.2116. This article has 81 citations.](https://doi.org/10.1038/nsmb.2116)

[17. (Lafrance-Vanasse2015Envisioning) Julien Lafrance-Vanasse, Gareth J. Williams, and John A. Tainer. Envisioning the dynamics and flexibility of mre11-rad50-nbs1 complex to decipher its roles in dna replication and repair. Progress in Biophysics and Molecular Biology, 117(2–3):182–193, March 2015. URL: http://dx.doi.org/10.1016/j.pbiomolbio.2014.12.004, doi:10.1016/j.pbiomolbio.2014.12.004. This article has 137 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.pbiomolbio.2014.12.004)