Rad50

{{Short description|Protein-coding gene in the species Homo sapiens}}

DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.{{cite web | title = Entrez Gene: RAD50 RAD50 homolog (S. cerevisiae)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10111}}

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.

Structure

Rad50 is a member of the structural maintenance of chromosomes (SMC) family of proteins.{{cite journal |vauthors=Kinoshita E, van der Linden E, Sanchez H, Wyman C | title = RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function? | journal = Chromosome Res. | volume = 17 | issue = 2 | pages = 277–88 | year = 2009 | pmid = 19308707 | pmc = 4494100 | doi = 10.1007/s10577-008-9018-6 }} 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”.{{cite journal |vauthors=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 | title = The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair | journal = Nature | volume = 418 | issue = 6897 | pages = 562–6 |date=August 2002 | pmid = 12152085 | doi = 10.1038/nature00922 | bibcode = 2002Natur.418..562H | s2cid = 4414704 }} 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.{{cite journal |vauthors=Moreno-Herrero F, de Jager M, Dekker NH, Kanaar R, Wyman C, Dekker C | title = Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA | journal = Nature | volume = 437 | issue = 7057 | pages = 440–3 |date=September 2005 | pmid = 16163361 | doi = 10.1038/nature03927 | bibcode = 2005Natur.437..440M | s2cid = 4357195 }}

Interactions

Rad50 has been shown to interact with:

BRCA1,{{cite journal |vauthors=Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH | title = Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response | journal = Science | volume = 285 | issue = 5428 | pages = 747–50 | year = 1999 | pmid = 10426999 | doi = 10.1126/science.285.5428.747}}
MRE11A,{{cite journal |vauthors=Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J | title = BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures | journal = Genes Dev. | volume = 14 | issue = 8 | pages = 927–39 | year = 2000 | pmid = 10783165 | pmc = 316544 | doi = 10.1101/gad.14.8.927}}{{cite journal |vauthors=Chiba N, Parvin JD | title = Redistribution of BRCA1 among four different protein complexes following replication blockage | journal = J. Biol. Chem. | volume = 276 | issue = 42 | pages = 38549–54 | year = 2001 | pmid = 11504724 | doi = 10.1074/jbc.M105227200 | doi-access = free }}{{cite journal |vauthors=Dolganov GM, Maser RS, Novikov A, Tosto L, Chong S, Bressan DA, Petrini JH | title = Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair | journal = Mol. Cell. Biol. | volume = 16 | issue = 9 | pages = 4832–41 | year = 1996 | pmid = 8756642 | pmc = 231485 | doi = 10.1128/MCB.16.9.4832}}{{cite journal |author3-link=Eva Y.-H. P. Lee |vauthors=Trujillo KM, Yuan SS, Lee EY, Sung P | title = Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95 | journal = J. Biol. Chem. | volume = 273 | issue = 34 | pages = 21447–50 | year = 1998 | pmid = 9705271 | doi = 10.1074/jbc.273.34.21447| doi-access = free }}{{cite journal |vauthors=Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C | title = Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis | journal = Nat. Genet. | volume = 23 | issue = 2 | pages = 194–8 | year = 1999 | pmid = 10508516 | doi = 10.1038/13821 | s2cid = 13443404 }}
NBN,{{cite journal |vauthors=Cerosaletti KM, Concannon P | title = Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation | journal = J. Biol. Chem. | volume = 278 | issue = 24 | pages = 21944–51 | year = 2003 | pmid = 12679336 | doi = 10.1074/jbc.M211689200 | doi-access = free }}{{cite journal |vauthors=Desai-Mehta A, Cerosaletti KM, Concannon P | title = Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization | journal = Mol. Cell. Biol. | volume = 21 | issue = 6 | pages = 2184–91 | year = 2001 | pmid = 11238951 | pmc = 86852 | doi = 10.1128/MCB.21.6.2184-2191.2001 }}
RINT1,{{cite journal |vauthors=Xiao J, Liu CC, Chen PL, Lee WH | title = RINT-1, a novel Rad50-interacting protein, participates in radiation-induced G(2)/M checkpoint control | journal = J. Biol. Chem. | volume = 276 | issue = 9 | pages = 6105–11 | year = 2001 | pmid = 11096100 | doi = 10.1074/jbc.M008893200 | doi-access = free }}
TERF2IP,{{cite journal |vauthors=O'Connor MS, Safari A, Liu D, Qin J, Songyang Z | title = The human Rap1 protein complex and modulation of telomere length | journal = J. Biol. Chem. | volume = 279 | issue = 27 | pages = 28585–91 | year = 2004 | pmid = 15100233 | doi = 10.1074/jbc.M312913200 | doi-access = free }} and
TERF2.{{cite journal |vauthors=Zhu XD, Küster B, Mann M, Petrini JH, de Lange T | title = Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres | journal = Nat. Genet. | volume = 25 | issue = 3 | pages = 347–52 | year = 2000 | pmid = 10888888 | doi = 10.1038/77139 | s2cid = 6689794 }}

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.{{cite journal | author = White MF | title = Homologous recombination in the archaea: the means justify the ends | journal = Biochem. Soc. Trans. | volume = 39 | issue = 1 | pages = 15–9 |date=January 2011 | pmid = 21265740 | doi = 10.1042/BST0390015 | s2cid = 239399 }} 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.{{cite journal |vauthors=Quaiser A, Constantinesco F, White MF, Forterre P, Elie C | title = 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 | journal = BMC Mol. Biol. | volume = 9 | pages = 25 | year = 2008 | pmid = 18294364 | pmc = 2288612 | doi = 10.1186/1471-2199-9-25 | doi-access = free }} 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.

In yeast, the functions controlled by the RAD50 gene are essential for normal meiosis.{{cite journal |vauthors=Game JC, Zamb TJ, Braun RJ, Resnick M, Roth RM |title=The Role of Radiation (rad) Genes in Meiotic Recombination in Yeast |journal=Genetics |volume=94 |issue=1 |pages=51–68 |date=January 1980 |pmid=17248996 |pmc=1214137 |doi=10.1093/genetics/94.1.51 |url=}} It appears that the normal functions specified by RAD50 are not essential for either the initial or terminal steps in meiosis, but are required for successful recombination.

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. {{cite journal |vauthors=Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, Wieland B, Varon R, Lerenthal Y, Lavin MF, Schindler D, Dörk T | title = Human RAD50 deficiency in a Nijmegen Breakage Syndrome-like disorder | journal = Am. J. Hum. Genet. | volume = 84 | issue = 5 | pages = 605–16 | year = 2009 | doi = 10.1016/j.ajhg.2009.04.010 | pmid = 19409520 | pmc = 2681000 }}{{cite journal |vauthors=Ragamin A, Yigit G, Bousset K, Beleggia F, Verheijen FW, de Wit MY, Strom TM, Dörk T, Wollnik B, Mancini GM | title = Human RAD50 deficiency: Confirmation of a distinctive phenotype | journal = Am. J. Med. Genet. | volume = 182 | issue = 6 | pages = 1378–86 | year = 2020 | doi = 10.1002/ajmg.a.61570 | pmid = 32212377 | pmc = 7318339 }}{{cite journal |vauthors=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 | title = A Disease-Causing Single Amino Acid Deletion in the Coiled-Coil Domain of RAD50 Impairs MRE11 Complex Functions in Yeast and Humans | journal = Cell Rep. | volume = 33 | issue = 13 | page = 108559 | year = 2020 | doi = 10.1016/j.celrep.2020.108559 | pmid = 33378670 | pmc = 7788285 }}

References

External links

{{UCSC genome browser|RAD50}}
{{UCSC gene details|RAD50}}