Rad50

RAD50
Identifiers
Aliases	RAD50, NBSLD, RAD502, hRad50, Rad50, RAD50 double strand break repair protein
External IDs	OMIM: 604040, 613078; MGI: 109292; HomoloGene: 38092; GeneCards: RAD50; OMA:RAD50 - orthologs
Gene location (Human)
Chr.	Chromosome 5 (human)
End	132,646,349 bp
Gene location (Mouse)
Chr.	Chromosome 11 (mouse)
End	53,598,146 bp
RNA expression pattern
	Top expressed in
	corpus callosum; ; Achilles tendon; ; epithelium of colon; ; testicle; ; gonad; ; islet of Langerhans; ; stromal cell of endometrium; ; ventricular zone; ; tonsil; ; sural nerve;
	Top expressed in
	tail of embryo; ; genital tubercle; ; zygote; ; primary oocyte; ; secondary oocyte; ; internal carotid artery; ; Ileal epithelium; ; epiblast; ; Paneth cell; ; ovary;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	DNA binding; protein-macromolecule adaptor activity; nucleotide binding; DNA helicase activity; metal ion binding; single-stranded DNA endodeoxyribonuclease activity; ATPase activity; protein binding; 3'-5' exonuclease activity; hydrolase activity; ATP binding; double-stranded telomeric DNA binding; adenylate kinase activity; G-quadruplex DNA binding; single-stranded telomeric DNA binding;
Cellular component	site of double-strand break; membrane; nucleoplasm; chromosome; telomere; nucleus; condensed nuclear chromosome; Mre11 complex;
Biological process	reciprocal meiotic recombination; DNA recombination; telomere maintenance via telomerase; positive regulation of kinase activity; telomeric 3' overhang formation; cellular response to DNA damage stimulus; positive regulation of telomere maintenance; negative regulation of telomere capping; DNA duplex unwinding; meiosis; double-strand break repair; positive regulation of protein autophosphorylation; cell cycle; viral process; double-strand break repair via nonhomologous end joining; telomere maintenance; regulation of mitotic recombination; nucleic acid phosphodiester bond hydrolysis; DNA replication; DNA double-strand break processing; telomere maintenance via recombination; DNA synthesis involved in DNA repair; chromosome organization involved in meiotic cell cycle; regulation of signal transduction by p53 class mediator; nucleotide phosphorylation; DNA repair; double-strand break repair via homologous recombination; strand displacement; telomere capping; nucleoside monophosphate phosphorylation;
	Sources:Amigo / QuickGO
Orthologs
	10111
	19360
	ENSG00000113522
	ENSMUSG00000020380
	Q92878
	P70388
	NM_133482; NM_005732
	NM_009012
	NP_005723
	n/a
	Wikidata
View/Edit Human	View/Edit Mouse

DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.^[5]

Function

The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1 (also known as Xrs2 in yeast). This MRN complex (MRX complex in yeast) binds to broken DNA ends and displays numerous enzymatic activities that are required for double-strand break repair by nonhomologous end-joining or homologous recombination. Gene knockout studies of the mouse homolog of Rad50 suggest it is essential for cell growth and viability. Two alternatively spliced transcript variants of Rad50, which encode distinct proteins, have been reported.^[5]

Structure

Rad50 is a member of the structural maintenance of chromosomes (SMC) family of proteins.^[6] Like other SMC proteins, Rad50 contains a long internal coiled-coil domain that folds back on itself, bringing the N- and C-termini together to form a globular ABC ATPase head domain. Rad50 can dimerize both through its head domain and through a zinc-binding dimerization motif at the opposite end of the coiled-coil known as the “zinc-hook”.^[7] Results from atomic force microscopy suggest that in free Mre11-Rad50-Nbs1 complexes, the zinc-hooks of a single Rad50 dimer associate to form a closed loop, while the zinc-hooks snap apart upon binding DNA, adopting a conformation that is thought to enable zinc-hook-mediated tethering of broken DNA ends.^[8]

Interactions

Rad50 has been shown to interact with:

BRCA1,^[9]^[10]^[11]
MRE11A,^[9]^[10]^[12]^[13]^[14]
NBN,^[9]^[13]^[15]^[16]
RINT1,^[17]
TERF2IP,^[18] and
TERF2.^[18]^[19]

Evolutionary ancestry

Rad50 protein has been mainly studied in eukaryotes. However, recent work has shown that orthologs of the Rad50 protein are also conserved in extant prokaryotic archaea where they likely function in homologous recombinational repair.^[20] In the hyperthermophilic archeon Sulfolobus acidocaldarius, the Rad50 and Mre11 proteins interact and appear to have an active role in repair of DNA damages introduced by gamma radiation.^[21] These findings suggest that eukaryotic Rad50 may be descended from an ancestral archaeal Rad50 protein that served a role in homologous recombinational repair of DNA damage.

Diseases

Human RAD50 deficiency is an autosomal recessive syndrome that has been reported in patients with microcephaly and short stature. Their clinical phenotype resembled Nijmegen Breakage Syndrome. Cells from these patients showed increased radiosensitity with an impaired response to chromosome breaks. ^[22]^[23]^[24]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000113522 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000020380 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: RAD50 RAD50 homolog (S. cerevisiae)".
^ Kinoshita E, van der Linden E, Sanchez H, Wyman C (2009). "RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function?". Chromosome Res. 17 (2): 277–88. doi:10.1007/s10577-008-9018-6. PMC 4494100. PMID 19308707.
^ Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT, Carney JP, Petrini JH, Tainer JA (August 2002). "The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair". Nature. 418 (6897): 562–6. Bibcode:2002Natur.418..562H. doi:10.1038/nature00922. PMID 12152085. S2CID 4414704.
^ Moreno-Herrero F, de Jager M, Dekker NH, Kanaar R, Wyman C, Dekker C (September 2005). "Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA". Nature. 437 (7057): 440–3. Bibcode:2005Natur.437..440M. doi:10.1038/nature03927. PMID 16163361. S2CID 4357195.
^ ^a ^b ^c Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. doi:10.1101/gad.14.8.927. PMC 316544. PMID 10783165.
^ ^a ^b Chiba N, Parvin JD (2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724.
^ Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH (1999). "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response". Science. 285 (5428): 747–50. doi:10.1126/science.285.5428.747. PMID 10426999.
^ Dolganov GM, Maser RS, Novikov A, Tosto L, Chong S, Bressan DA, Petrini JH (1996). "Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair". Mol. Cell. Biol. 16 (9): 4832–41. doi:10.1128/MCB.16.9.4832. PMC 231485. PMID 8756642.
^ ^a ^b Trujillo KM, Yuan SS, Lee EY, Sung P (1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. PMID 9705271.
^ Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C (1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nat. Genet. 23 (2): 194–8. doi:10.1038/13821. PMID 10508516. S2CID 13443404.
^ Cerosaletti KM, Concannon P (2003). "Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation". J. Biol. Chem. 278 (24): 21944–51. doi:10.1074/jbc.M211689200. PMID 12679336.
^ Desai-Mehta A, Cerosaletti KM, Concannon P (2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. PMC 86852. PMID 11238951.
^ Xiao J, Liu CC, Chen PL, Lee WH (2001). "RINT-1, a novel Rad50-interacting protein, participates in radiation-induced G(2)/M checkpoint control". J. Biol. Chem. 276 (9): 6105–11. doi:10.1074/jbc.M008893200. PMID 11096100.
^ ^a ^b O'Connor MS, Safari A, Liu D, Qin J, Songyang Z (2004). "The human Rap1 protein complex and modulation of telomere length". J. Biol. Chem. 279 (27): 28585–91. doi:10.1074/jbc.M312913200. PMID 15100233.
^ Zhu XD, Küster B, Mann M, Petrini JH, de Lange T (2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. 25 (3): 347–52. doi:10.1038/77139. PMID 10888888. S2CID 6689794.
^ White MF (January 2011). "Homologous recombination in the archaea: the means justify the ends". Biochem. Soc. Trans. 39 (1): 15–9. doi:10.1042/BST0390015. PMID 21265740. S2CID 239399.
^ Quaiser A, Constantinesco F, White MF, Forterre P, Elie C (2008). "The Mre11 protein interacts with both Rad50 and the HerA bipolar helicase and is recruited to DNA following gamma irradiation in the archaeon Sulfolobus acidocaldarius". BMC Mol. Biol. 9: 25. doi:10.1186/1471-2199-9-25. PMC 2288612. PMID 18294364.
^ Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, Wieland B, Varon R, Lerenthal Y, Lavin MF, Schindler D, Dörk T (2009). "Human RAD50 deficiency in a Nijmegen Breakage Syndrome-like disorder". Am. J. Hum. Genet. 84 (5): 605–16. doi:10.1016/j.ajhg.2009.04.010. PMC 2681000. PMID 19409520.
^ Ragamin A, Yigit G, Bousset K, Beleggia F, Verheijen FW, de Wit MY, Strom TM, Dörk T, Wollnik B, Mancini GM (2020). "Human RAD50 deficiency: Confirmation of a distinctive phenotype". Am. J. Med. Genet. 182 (6): 1378–86. doi:10.1002/ajmg.a.61570. PMC 7318339. PMID 32212377.
^ Chansel-Da Cruz M, Hohl M, Ceppi I, Kermasson L, Maggiorella L, Modesti M, de Villartay J, Ileri T, Cejka P, Petrini J, Revy P (2020). "A Disease-Causing Single Amino Acid Deletion in the Coiled-Coil Domain of RAD50 Impairs MRE11 Complex Functions in Yeast and Humans". Cell Rep. 33 (13): 108559. doi:10.1016/j.celrep.2020.108559. PMC 7788285. PMID 33378670.

External links

RAD50 human gene location in the UCSC Genome Browser.
RAD50 human gene details in the UCSC Genome Browser.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000113522 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000020380 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: RAD50 RAD50 homolog (S. cerevisiae)".

[kinoshita_review-6] Kinoshita E, van der Linden E, Sanchez H, Wyman C (2009). "RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function?". Chromosome Res. 17 (2): 277–88. doi:10.1007/s10577-008-9018-6. PMC 4494100. PMID 19308707.

[pmid12152085-7] Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT, Carney JP, Petrini JH, Tainer JA (August 2002). "The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair". Nature. 418 (6897): 562–6. Bibcode:2002Natur.418..562H. doi:10.1038/nature00922. PMID 12152085. S2CID 4414704.

[pmid16163361-8] Moreno-Herrero F, de Jager M, Dekker NH, Kanaar R, Wyman C, Dekker C (September 2005). "Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA". Nature. 437 (7057): 440–3. Bibcode:2005Natur.437..440M. doi:10.1038/nature03927. PMID 16163361. S2CID 4357195.

[pmid10783165-9] Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. doi:10.1101/gad.14.8.927. PMC 316544. PMID 10783165.

[pmid11504724-10] Chiba N, Parvin JD (2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724.

[pmid10426999-11] Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH (1999). "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response". Science. 285 (5428): 747–50. doi:10.1126/science.285.5428.747. PMID 10426999.

[pmid8756642-12] Dolganov GM, Maser RS, Novikov A, Tosto L, Chong S, Bressan DA, Petrini JH (1996). "Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair". Mol. Cell. Biol. 16 (9): 4832–41. doi:10.1128/MCB.16.9.4832. PMC 231485. PMID 8756642.

[pmid9705271-13] Trujillo KM, Yuan SS, Lee EY, Sung P (1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. PMID 9705271.

[pmid-14] Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C (1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nat. Genet. 23 (2): 194–8. doi:10.1038/13821. PMID 10508516. S2CID 13443404.

[pmid12679336-15] Cerosaletti KM, Concannon P (2003). "Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation". J. Biol. Chem. 278 (24): 21944–51. doi:10.1074/jbc.M211689200. PMID 12679336.

[pmid11238951-16] Desai-Mehta A, Cerosaletti KM, Concannon P (2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. PMC 86852. PMID 11238951.

[pmid11096100-17] Xiao J, Liu CC, Chen PL, Lee WH (2001). "RINT-1, a novel Rad50-interacting protein, participates in radiation-induced G(2)/M checkpoint control". J. Biol. Chem. 276 (9): 6105–11. doi:10.1074/jbc.M008893200. PMID 11096100.

[pmid15100233-18] O'Connor MS, Safari A, Liu D, Qin J, Songyang Z (2004). "The human Rap1 protein complex and modulation of telomere length". J. Biol. Chem. 279 (27): 28585–91. doi:10.1074/jbc.M312913200. PMID 15100233.

[pmid10888888-19] Zhu XD, Küster B, Mann M, Petrini JH, de Lange T (2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. 25 (3): 347–52. doi:10.1038/77139. PMID 10888888. S2CID 6689794.

[pmid21265740-20] White MF (January 2011). "Homologous recombination in the archaea: the means justify the ends". Biochem. Soc. Trans. 39 (1): 15–9. doi:10.1042/BST0390015. PMID 21265740. S2CID 239399.

[pmid18294364-21] Quaiser A, Constantinesco F, White MF, Forterre P, Elie C (2008). "The Mre11 protein interacts with both Rad50 and the HerA bipolar helicase and is recruited to DNA following gamma irradiation in the archaeon Sulfolobus acidocaldarius". BMC Mol. Biol. 9: 25. doi:10.1186/1471-2199-9-25. PMC 2288612. PMID 18294364.

[pmid19409520-22] Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, Wieland B, Varon R, Lerenthal Y, Lavin MF, Schindler D, Dörk T (2009). "Human RAD50 deficiency in a Nijmegen Breakage Syndrome-like disorder". Am. J. Hum. Genet. 84 (5): 605–16. doi:10.1016/j.ajhg.2009.04.010. PMC 2681000. PMID 19409520.

[pmid32212377-23] Ragamin A, Yigit G, Bousset K, Beleggia F, Verheijen FW, de Wit MY, Strom TM, Dörk T, Wollnik B, Mancini GM (2020). "Human RAD50 deficiency: Confirmation of a distinctive phenotype". Am. J. Med. Genet. 182 (6): 1378–86. doi:10.1002/ajmg.a.61570. PMC 7318339. PMID 32212377.

[pmid33378670-24] Chansel-Da Cruz M, Hohl M, Ceppi I, Kermasson L, Maggiorella L, Modesti M, de Villartay J, Ileri T, Cejka P, Petrini J, Revy P (2020). "A Disease-Causing Single Amino Acid Deletion in the Coiled-Coil Domain of RAD50 Impairs MRE11 Complex Functions in Yeast and Humans". Cell Rep. 33 (13): 108559. doi:10.1016/j.celrep.2020.108559. PMC 7788285. PMID 33378670.

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