Effects of Tumor-associated Mutations on Rad54 Functions

Smirnova, Marina G.; Komen, Stephen Van; Sung, Patrick; Klein, Hannah L.

doi:10.1074/jbc.m402719200

Cited by 26 publications

(22 citation statements)

References 61 publications

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“…The dual functionality of Rad54p may have evolved as genomes became larger and more highly condensed chromatin structures began to interfere with HR. A mutation that disrupts the ATPase domain of human RAD54 is found in some tumors (29), suggesting that ATP-dependent chromatin remodeling by Rad54 may play a key role in maintaining genome integrity among all eukaryotes.…”

Section: Figmentioning

confidence: 99%

ATP-dependent and ATP-independent Roles for the Rad54 Chromatin Remodeling Enzyme during Recombinational Repair of a DNA Double Strand Break

Wolner

Peterson

2005

Journal of Biological Chemistry

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The efficient and accurate repair of DNA double strand breaks (DSBs) is critical to cell survival, and defects in this process can lead to genome instability and cancers. In eukaryotes, the Rad52 group of proteins dictates the repair of DSBs by the error-free process of homologous recombination (HR). A critical step in eukaryotic HR is the formation of the initial Rad51-singlestranded DNA presynaptic nucleoprotein filament. This presynaptic filament participates in a homology search process that leads to the formation of a DNA joint molecule and recombinational repair of the DSB. Recently, we showed that the Rad54 protein functions as a mediator of Rad51 binding to single-stranded DNA, and here, we find that this activity does not require ATP hydrolysis. We also identify a novel Rad54-dependent chromatin remodeling event that occurs in vivo during the DNA strand invasion step of HR. This ATP-dependent remodeling activity of Rad54 appears to control subsequent steps in the HR process. Double strand breaks (DSBs)1 are a common form of DNA damage, resulting from a variety of environmental insults including ionizing radiation and chemical attack. The most common cause of DSBs is internal reactive oxygen species, accounting for thousands of breaks per cell per day. The inability to repair these breaks leads to genomic instability. Misrepair of these breaks can result in deletions, insertions, and translocations. In higher eukaryotes, improper DSB repair can lead to tumorigenesis. It is therefore of vital importance that cells repair these breaks accurately and faithfully.Several pathways have evolved for the repair of DSBs. In yeast, the predominant pathway is thought to be homologous recombination (1, 2). Homologous recombination (HR) provides an "error-free" method for repairing DSBs as it utilizes homologous DNA sequences as a template to repair the lesion with no loss of genetic information. The genes in the RAD52 epistasis group, required for HR, are highly conserved from yeast to man (2-4), highlighting the importance of this molecular pathway.Studies in yeast have suggested a sequence of molecular events that occur following the formation of a DSB (2, 4, 5). Nucleolytic end processing leads to resection of the 5Ј ends of DNA that flank the break, generating long stretches of 3Ј single-stranded DNA. Rad51p binds the single-stranded DNA, forming right-handed helical nucleoprotein filaments. In vitro, Rad52p (6), Rad54p (7), and a Rad55p/Rad57p heterodimer (8) mediate this early step by overcoming the inhibitory effects of the heterotrimeric single-stranded DNA-binding protein, RPA.In vivo, these same Rad proteins are also required for optimal recruitment of Rad51p to DNA surrounding a single DSB in yeast (7, 9). The Rad51-nucleoprotein filament is believed to search the genome for homologous sequences, resulting in the formation of a heteroduplex "joint molecule" (10). Joint molecule formation is followed by extension of the incoming strand by DNA polymerases and branch migration. The end result is the repair of...

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Section: Figmentioning

confidence: 99%

ATP-dependent and ATP-independent Roles for the Rad54 Chromatin Remodeling Enzyme during Recombinational Repair of a DNA Double Strand Break

Wolner

Peterson

2005

Journal of Biological Chemistry

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“…The homologous recombination pathway and its associated upstream gatekeeper molecules oversee the error-free DNA reconstruction of double-stranded lesions (10)(11)(12)(13)(14)(15). Indeed, the most penetrant breast cancer genes identified thus far, BRCA1, BRCA2, and CHEK2, play major roles in DNA repair, although common variants in these genes confer no significant risk of breast cancer (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Common Single-Nucleotide Polymorphisms in DNA Double-Strand Break Repair Genes and Breast Cancer Risk

Pooley

Baynes

Driver

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The proteins involved in homologous recombination are instrumental in the error-free repair of dsDNA breakages, and common germ-line variations in these genes are, therefore, potential candidates for involvement in breast cancer development and progression. We carried out a search for common, low-penetrance susceptibility alleles by tagging the common variation in 13 genes in this pathway in a two-stage case-control study. We genotyped 100 single-nucleotide polymorphisms (SNP), tagging the 655 common SNPs in these genes, in up to 4,470 cases and 4,560 controls from the SEARCH study. None of these tagging SNPs was associated with breast cancer risk, with the exception of XRCC2 rs3218536, R188H, which showed some evidence of a protective association for the rare allele [per allele odds ratio, 0.89; 95% confidence intervals (95% CI), 0.80-0.99; P trend = 0.03]. Further analyses showed that this effect was confined to a risk of progesterone receptor positive tumors (per rare allele odds ratio, 0.78; 95% CI, 0.66-0.91; P trend = 0.002). Several other SNPs also showed receptor status-specific susceptibility and evidence of roles in long-term survival, with the rare allele of BRIP1 rs2191249 showing evidence of association with a poorer prognosis (hazard ratio per minor allele, 1.20; 95% CI, 1.07-1.36; P trend = 0.002). In summary, there was little evidence of breast cancer susceptibility with any of the SNPs studied, but larger studies would be needed to confirm subgroup effects. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3482 -9)

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“…RAD54B was chosen because homozygous mutations at highly conserved positions have been identified in human primary lymphoma and colon cancers (18), although the functional status of these mutant alleles has not been directly tested in a mammalian context (19). Furthermore, RAD54B exhibits a significant degree of sequence and functional similarity with yeast Rdh54 and Rad54 which both exhibit strong CIN phenotypes in yeast (20).…”

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confidence: 99%

Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing

McManus

Barrett

Nouhi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

119

131

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Mutations that cause chromosome instability (CIN) in cancer cells produce ''sublethal'' deficiencies in an essential process (chromosome segregation) and, therefore, may represent a major untapped resource that could be exploited for therapeutic benefit in the treatment of cancer. If second-site unlinked genes can be identified, that when knocked down, cause a synthetic lethal (SL) phenotype in combination with a somatic mutation in a CIN gene, novel candidate therapeutic targets will be identified. To test this idea, we took a cross species SL candidate gene approach by recapitulating a SL interaction observed between rad54 and rad27 mutations in yeast, via knockdown of the highly sequence-and functionally-related proteins RAD54B and FEN1 in a cancer cell line. We show that knockdown of RAD54B, a gene known to be somatically mutated in cancer, causes CIN in mammalian cells. Using high-content microscopy techniques, we demonstrate that RAD54B-deficient human colorectal cancer cells are sensitive to SL killing by reduced FEN1 expression, while isogenic RAD54B proficient cells are not. This conserved SL interaction suggests that extrapolating SL interactions observed in model organisms for homologous genes mutated in human cancers will aid in the identification of novel therapeutic targets for specific killing of cancerous cells exhibiting CIN.cancer therapeutics ͉ chromosome instability ͉ synthetic lethality

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Effects of Tumor-associated Mutations on Rad54 Functions

Cited by 26 publications

References 61 publications

ATP-dependent and ATP-independent Roles for the Rad54 Chromatin Remodeling Enzyme during Recombinational Repair of a DNA Double Strand Break

ATP-dependent and ATP-independent Roles for the Rad54 Chromatin Remodeling Enzyme during Recombinational Repair of a DNA Double Strand Break

Common Single-Nucleotide Polymorphisms in DNA Double-Strand Break Repair Genes and Breast Cancer Risk

Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing

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