RAD54L

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
Gene location (Human)
Chr.	Chromosome 1 (human)
End	46,278,480 bp
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)
End	115,980,887 bp
RNA expression pattern
	Top expressed in
	ganglionic eminence; ; cerebellar hemisphere; ; gastrocnemius muscle; ; stromal cell of endometrium; ; secondary oocyte; ; rectum; ; appendix; ; thymus; ; Brodmann area 9; ; nucleus accumbens;
	Top expressed in
	primitive streak; ; otic placode; ; maxillary prominence; ; abdominal wall; ; blastocyst; ; medial ganglionic eminence; ; saccule; ; ureter; ; ascending aorta; ; somite;
	More reference expression data
	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
	8438
	19366
	ENSG00000085999
	ENSMUSG00000028702
	Q92698
	P70270
	NM_001142548 ; NM_003579 ; NM_001370766
	NM_001122958 ; NM_001122959 ; NM_009015
	NP_001136020 ; NP_003570 ; NP_001357695
	NP_001116430 ; NP_001116431 ; NP_033041
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated February 25, 2024

DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54L gene.^[5]^[6]

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.^[6]

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.^[7] 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.^[7]

Related Research Articles

Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H₂O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H₂O → NDP + P to drive the unwinding of either DNA or RNA.

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive alleles in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive alleles. Mitotic homologous recombination occurs mainly between sister chromatids subsequent to replication. Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous chromatids is only about 1% of that between sister chromatids.

<span class="mw-page-title-main">RAD51</span>

DNA repair protein RAD51 homolog 1 is a protein encoded by the gene RAD51. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA, Archaeal RadA and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans.

Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.

Probable global transcription activator SNF2L2 is a protein that in humans is encoded by the SMARCA2 gene.

Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.

RAD52 homolog , also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.

RAD51 homolog C , also known as RAD51C, is a protein which in humans is encoded by the RAD51C gene.

DNA repair protein RAD51 homolog 4 is a protein that in humans is encoded by the RAD51L3 gene.

DNA repair protein XRCC2 is a protein that in humans is encoded by the XRCC2 gene.

MutS protein homolog 5 is a protein that in humans is encoded by the MSH5 gene.

Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene.

MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene.

Structural maintenance of chromosomes protein 6 is a protein that in humans is encoded by the SMC6 gene.

DNA repair and recombination protein RAD54B is a protein that in humans is encoded by the RAD54B gene.

Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.

Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1983 was favored by many researchers. In 1994, studies of double-strand gap repair in Drosophila were found to be incompatible with the double-Holliday junction model, leading researchers to propose a model they called synthesis-dependent strand annealing. Subsequent studies of meiotic recombination in S. cerevisiae found that non-crossover products appear earlier than double-Holliday junctions or crossover products, challenging the previous notion that both crossover and non-crossover products are produced by double-Holliday junctions and leading the authors to propose that non-crossover products are generated through SDSA.

A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000085999 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028702 - 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.
↑ 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.
1 2 "Entrez Gene: RAD54L RAD54-like (S. cerevisiae)".
1 2 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.

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.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000085999 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 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.

[pmid8805304-5] 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.

[entrez-6] 1 2 "Entrez Gene: RAD54L RAD54-like (S. cerevisiae)".

[Russo_2018-7] 1 2 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.

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