DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene. [5]
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene. [5]
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]
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]
Rad50 has been shown to interact with:
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.
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]
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.
A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.
Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.
H2A histone family member X is a type of histone protein from the H2A family encoded by the H2AFX gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
Replication protein A 70 kDa DNA-binding subunit is a protein that in humans is encoded by the RPA1 gene.
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the MRE11 gene. The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.
DNA replication licensing factor MCM4 is a protein that in humans is encoded by the MCM4 gene.
Transformation/transcription domain-associated protein, also known as TRRAP, is a protein that in humans is encoded by the TRRAP gene. TRRAP belongs to the phosphatidylinositol 3-kinase-related kinase protein family.
Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.
C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the CTBP1 gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2.
Fanconi anemia group G protein is a protein that in humans is encoded by the FANCG gene.
Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1).
Retinoblastoma-binding protein 8 is a protein that in humans is encoded by the RBBP8 gene.
DNA repair protein RAD51 homolog 4 is a protein that in humans is encoded by the RAD51L3 gene.
Telomeric repeat-binding factor 2-interacting protein 1 also known as repressor activator protein 1 (Rap1) is a protein that in humans is encoded by the TERF2IP gene.
E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.
E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair.
DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8 gene.
The MRN complex is a protein complex consisting of Mre11, Rad50 and Nbs1. In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-strand DNA breaks prior to repair by homologous recombination or non-homologous end joining. The MRN complex binds avidly to double-strand breaks both in vitro and in vivo and may serve to tether broken ends prior to repair by non-homologous end joining or to initiate DNA end resection prior to repair by homologous recombination. The MRN complex also participates in activating the checkpoint kinase ATM in response to DNA damage. Production of short single-strand oligonucleotides by Mre11 endonuclease activity has been implicated in ATM activation by the MRN complex.