DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54Lgene.[1][2]
The protein encoded by this gene belongs to the DEAD-like helicase superfamily, and shares similarity with Saccharomyces cerevisiae Rad54, a protein known to be involved in the homologous recombination and repair of DNA. This protein has been shown to play a role in homologous recombination related repair of DNA double-strand breaks. The binding of this protein to double-strand DNA induces a DNA topological change, which is thought to facilitate homologous DNA pairing, and stimulate DNA recombination.[2]
RAD54 is one of the key proteins necessary for homologous recombination and DNA repair in many organisms. Without functional RAD54, tumor development is more likely. RAD54 was initially described in the budding yeast Saccharomyces cerevisiae as being a member of the evolutionarily conserved RAD52 epistasis group, which additionally includes RAD51, RAD52, RAD55, and RAD57 factors. This group is believed to be involved in DNA recombination events and repair mechanisms, especially those involving double-stranded DNA breaks during both mitosis and meiosis. Recently a human homologue of the yeast RAD54 was discovered and termed hRAD54.
Human RAD54 (hRAD54)
Human RAD54, or hRAD54, is linked to chromosome 1p32. It encodes a protein, composed of 747 amino acids, that is 52% identical to its yeast counterpart. These two proteins also share many functional similarities. The RAD54 encoded product is a member of the Swi2/Snf2 protein family, a member of the Swi2/Snf2 subfamily of ATPases. These protein products have homology in seven conserved helicase motifs. Purified hRAD54 has been shown to specifically exhibit DNA-dependent ATPase and supercoiling activities. hRAD54 transcripts are expressed primarily in the testis and thymus, with lower levels being found also in the small intestines, colon, breast, and prostate. Mutants of hRAD54 are extremely sensitive to x-rays, as well as methyl methanesulfonate (MMS). These mutants are most likely defective in both the spontaneous and induced mitotic recombination processes.
Actions of hRAD54
The interaction between RAD54 and RAD51, another member of the RAD52 epistasis group, in humans is mediated by the N-terminal domain of the hRAD54 protein. This N-terminal end interacts with both the free and bound ends of the RAD51 protein. RAD54 moves along the length of the DNA, producing positive supercoils ahead of the replication protein movement and negative supercoils trailing the complex. The interaction with RAD51 enhances the ability of RAD54 to perform this supercoiling and strained opening activity. These proteins also work together to form DNA joints, with RAD54 specifically extending the joints and stabilizing the D-loops formed. An alternative function of RAD54 may be to remove RAD51 proteins after joints formation and recombination initiation has occurred.
Inactivation of hRAD54 and Cancer Susceptibility
Defects in RAD51 are known to be associated with tumor development. Normally, RAD51 interacts with both BRCA1 and BRCA2 protein products to cause tumor suppression. This leads to the assumption that other members of the RAD52 epistasis group, including RAD54, are also important in tumor development and suppression because of their homologous relationship. RAD54’s involvement as a necessary recombinational protein is supported in the finding that there are mutations of RAD54 in a small percentage of studied breast and colon carcinomas, as well as several lymphomas.
References
↑Kanaar R, Troelstra C, Swagemakers SM, Essers J, Smit B, Franssen JH, Pastink A, Bezzubova OY, Buerstedde JM, Clever B, Heyer WD, Hoeijmakers JH (Feb 1997). "Human and mouse homologs of the Saccharomyces cerevisiae RAD54 DNA repair gene: evidence for functional conservation". Curr Biol. 6 (7): 828–38. doi:10.1016/S0960-9822(02)00606-1. PMID8805304.
Rasio D, Murakumo Y, Robbins D, et al. (1997). "Characterization of the human homologue of RAD54: a gene located on chromosome 1p32 at a region of high loss of heterozygosity in breast tumors". Cancer Res. 57 (12): 2378–83. PMID9192813.
Sigurdsson S, Van Komen S, Petukhova G, Sung P (2003). "Homologous DNA pairing by human recombination factors Rad51 and Rad54". J. Biol. Chem. 277 (45): 42790–4. doi:10.1074/jbc.M208004200. PMID12205100.
Swagemakers SM, Essers J, de Wit J, et al. (1998). "The human RAD54 recombinational DNA repair protein is a double-stranded DNA-dependent ATPase". J. Biol. Chem. 273 (43): 28292–7. doi:10.1074/jbc.273.43.28292. PMID9774452.
Further reading
Rasio D, Murakumo Y, Robbins D, et al. (1997). "Characterization of the human homologue of RAD54: a gene located on chromosome 1p32 at a region of high loss of heterozygosity in breast tumors". Cancer Res. 57 (12): 2378–83. PMID9192813.
Swagemakers SM, Essers J, de Wit J, et al. (1998). "The human RAD54 recombinational DNA repair protein is a double-stranded DNA-dependent ATPase". J. Biol. Chem. 273 (43): 28292–7. doi:10.1074/jbc.273.43.28292. PMID9774452.
Matsuda M, Miyagawa K, Takahashi M, et al. (1999). "Mutations in the RAD54 recombination gene in primary cancers". Oncogene. 18 (22): 3427–30. doi:10.1038/sj.onc.1202692. PMID10362365.
Bello MJ, de Campos JM, Vaquero J, et al. (2000). "hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas". Cancer Genet. Cytogenet. 116 (2): 142–7. doi:10.1016/S0165-4608(99)00122-3. PMID10640146.
Pluth JM, Fried LM, Kirchgessner CU (2001). "Severe combined immunodeficient cells expressing mutant hRAD54 exhibit a marked DNA double-strand break repair and error-prone chromosome repair defect". Cancer Res. 61 (6): 2649–55. PMID11289143.
Sigurdsson S, Van Komen S, Petukhova G, Sung P (2003). "Homologous DNA pairing by human recombination factors Rad51 and Rad54". J. Biol. Chem. 277 (45): 42790–4. doi:10.1074/jbc.M208004200. PMID12205100.
Kim J, Bhinge AA, Morgan XC, Iyer VR (2005). "Mapping DNA-protein interactions in large genomes by sequence tag analysis of genomic enrichment". Nat. Methods. 2 (1): 47–53. doi:10.1038/nmeth726. PMID15782160.
Thomä NH, Czyzewski BK, Alexeev AA, et al. (2005). "Structure of the SWI2/SNF2 chromatin-remodeling domain of eukaryotic Rad54". Nat. Struct. Mol. Biol. 12 (4): 350–6. doi:10.1038/nsmb919. PMID15806108.
Al-Wahiby S, Wong HP, Slijepcevic P (2005). "Shortened telomeres in murine scid cells expressing mutant hRAD54 coincide with reduction in recombination at telomeres". Mutat. Res. 578 (1–2): 134–42. doi:10.1016/j.mrfmmm.2005.04.008. PMID15975611.
Gregory SG, Barlow KF, McLay KE, et al. (2006). "The DNA sequence and biological annotation of human chromosome 1". Nature. 441 (7091): 315–21. doi:10.1038/nature04727. PMID16710414.
Bugreev DV, Mazina OM, Mazin AV (2006). "Rad54 protein promotes branch migration of Holliday junctions". Nature. 442 (7102): 590–3. doi:10.1038/nature04889. PMID16862129.