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RAD54L
Identifiers
Aliases	RAD54L, HR54, RAD54A, hHR54, hRAD54, RAD54-like (S. cerevisiae), RAD54 like (S. cerevisiae), RAD54 like
External IDs	OMIM: 603615; MGI: 894697; HomoloGene: 48227; GeneCards: RAD54L; OMA:RAD54L - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1p34.1 Start 46,246,461 bp End 46,278,480 bp
Gene location (Mouse) Chr. Chromosome 4 (mouse) Band 4|4 D1 Start 115,951,461 bp End 115,980,887 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left testis right testis ventricular zone ganglionic eminence gonad testicle mucosa of transverse colon cerebellar hemisphere right hemisphere of cerebellum gastrocnemius muscle Top expressed in primitive streak otic placode otic vesicle tail of embryo tibiofemoral joint maxillary prominence mandibular prominence fetal liver hematopoietic progenitor cell epiblast genital tubercle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ATP-dependent DNA/DNA annealing activity DNA binding nucleotide binding protein binding hydrolase activity ATP binding helicase activity Cellular component nucleoplasm nucleus protein-containing complex Biological process response to ionizing radiation DNA recombination double-strand break repair double-strand break repair via homologous recombination determination of adult lifespan chromosome organization cellular response to DNA damage stimulus DNA repair meiosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8438 19366 Ensembl ENSG00000085999 ENSMUSG00000028702 UniProt Q92698 P70270 RefSeq (mRNA) NM_001142548 NM_003579 NM_001370766 NM_001122958 NM_001122959 NM_009015 RefSeq (protein) NP_001136020 NP_003570 NP_001357695 NP_001116430 NP_001116431 NP_033041 Location (UCSC) Chr 1: 46.25 – 46.28 Mb Chr 4: 115.95 – 115.98 Mb PubMed search
Wikidata
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DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54L gene.

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.

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 gene

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.

Function

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 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.

Meiosis

The frequency of spontaneous chromosome breaks during meiosis was measured in the spermatocytes of both wild type mice and Rad54/Rad54B knockout mice. In the Rad54/Rad54B knockout mice, the spontaneous chromosome aberration frequency detected at metaphase 1 of meiosis was more than 10-fold higher than in the wild-type mice. This finding, and additional experimental findings, indicated that the RAD54/RAD54B proteins have a role in maintaining a stable karyotype during male meiosis.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000085999 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000028702 – 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.
5. Kanaar R, Troelstra C, Swagemakers SM, Essers J, Smit B, Franssen JH, et al. (July 1996). "Human and mouse homologs of the Saccharomyces cerevisiae RAD54 DNA repair gene: evidence for functional conservation". Current Biology. 6 (7): 828–838. doi:10.1016/S0960-9822(02)00606-1. hdl:1765/3104. PMID 8805304. S2CID 2195913.
6. ^ "Entrez Gene: RAD54L RAD54-like (S. cerevisiae)".
7. ^ Russo A, Cordelli E, Salvitti T, Palumbo E, Pacchierotti F (October 2018). "Rad54/Rad54B deficiency is associated to increased chromosome breakage in mouse spermatocytes". Mutagenesis. 33 (4): 323–332. doi:10.1093/mutage/gey027. PMID 30204892.

Further reading

• Rasio D, Murakumo Y, Robbins D, Roth T, Silver A, Negrini M, et al. (June 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 Research. 57 (12): 2378–2383. PMID 9192813.
• Golub EI, Kovalenko OV, Gupta RC, Ward DC, Radding CM (October 1997). "Interaction of human recombination proteins Rad51 and Rad54". Nucleic Acids Research. 25 (20): 4106–4110. doi:10.1093/nar/25.20.4106. PMC 147015. PMID 9321665.
• Swagemakers SM, Essers J, de Wit J, Hoeijmakers JH, Kanaar R (October 1998). "The human RAD54 recombinational DNA repair protein is a double-stranded DNA-dependent ATPase". The Journal of Biological Chemistry. 273 (43): 28292–28297. doi:10.1074/jbc.273.43.28292. hdl:1765/8917. PMID 9774452.
• Matsuda M, Miyagawa K, Takahashi M, Fukuda T, Kataoka T, Asahara T, et al. (June 1999). "Mutations in the RAD54 recombination gene in primary cancers". Oncogene. 18 (22): 3427–3430. doi:10.1038/sj.onc.1202692. PMID 10362365. S2CID 36652599.
• Carling T, Imanishi Y, Gaz RD, Arnold A (September 1999). "Analysis of the RAD54 gene on chromosome 1p as a potential tumor-suppressor gene in parathyroid adenomas". International Journal of Cancer. 83 (1): 80–82. doi:10.1002/(SICI)1097-0215(19990924)83:1<80::AID-IJC15>3.0.CO;2-E. PMID 10449612.
• Bello MJ, de Campos JM, Vaquero J, Ruiz-Barnés P, Kusak ME, Sarasa JL, Rey JA (January 2000). "hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas". Cancer Genetics and Cytogenetics. 116 (2): 142–147. doi:10.1016/S0165-4608(99)00122-3. PMID 10640146.
• Pluth JM, Fried LM, Kirchgessner CU (March 2001). "Severe combined immunodeficient cells expressing mutant hRAD54 exhibit a marked DNA double-strand break repair and error-prone chromosome repair defect". Cancer Research. 61 (6): 2649–2655. PMID 11289143.
• Ristic D, Wyman C, Paulusma C, Kanaar R (July 2001). "The architecture of the human Rad54-DNA complex provides evidence for protein translocation along DNA". Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8454–8460. Bibcode:2001PNAS...98.8454R. doi:10.1073/pnas.151056798. PMC 37457. PMID 11459989.
• Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA, Dynlacht BD (January 2002). "E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints". Genes & Development. 16 (2): 245–256. doi:10.1101/gad.949802. PMC 155321. PMID 11799067.
• Sigurdsson S, Van Komen S, Petukhova G, Sung P (November 2002). "Homologous DNA pairing by human recombination factors Rad51 and Rad54". The Journal of Biological Chemistry. 277 (45): 42790–42794. doi:10.1074/jbc.M208004200. PMID 12205100.
• Leone PE, Mendiola M, Alonso J, Paz-y-Miño C, Pestaña A (March 2003). "Implications of a RAD54L polymorphism (2290C/T) in human meningiomas as a risk factor and/or a genetic marker". BMC Cancer. 3: 6. doi:10.1186/1471-2407-3-6. PMC 152652. PMID 12614485.
• Kim J, Bhinge AA, Morgan XC, Iyer VR (January 2005). "Mapping DNA-protein interactions in large genomes by sequence tag analysis of genomic enrichment". Nature Methods. 2 (1): 47–53. doi:10.1038/nmeth726. PMID 15782160. S2CID 6135437.
• Thomä NH, Czyzewski BK, Alexeev AA, Mazin AV, Kowalczykowski SC, Pavletich NP (April 2005). "Structure of the SWI2/SNF2 chromatin-remodeling domain of eukaryotic Rad54". Nature Structural & Molecular Biology. 12 (4): 350–356. doi:10.1038/nsmb919. PMID 15806108. S2CID 3226377.
• Al-Wahiby S, Wong HP, Slijepcevic P (October 2005). "Shortened telomeres in murine scid cells expressing mutant hRAD54 coincide with reduction in recombination at telomeres". Mutation Research. 578 (1–2): 134–142. doi:10.1016/j.mrfmmm.2005.04.008. PMID 15975611.
• Bugreev DV, Mazina OM, Mazin AV (August 2006). "Rad54 protein promotes branch migration of Holliday junctions". Nature. 442 (7102): 590–593. Bibcode:2006Natur.442..590B. doi:10.1038/nature04889. PMID 16862129. S2CID 4324847.
• Akiyama K, Yusa K, Hashimoto H, Poonepalli A, Hande MP, Kakazu N, et al. (November 2006). "Rad54 is dispensable for the ALT pathway". Genes to Cells. 11 (11): 1305–1315. doi:10.1111/j.1365-2443.2006.01020.x. PMID 17054727. S2CID 34879148.

• Genes on human chromosome 1