Telomere Maintenance Requires the RAD51D Recombination/Repair Protein

Tarsounas, Madalena; Muñoz, Purificacı́on; Claas, Andreas; Smiraldo, Phillip G.; Pittman, Douglas L.; Blasco, Marı́a A.; West, Stephen C.

doi:10.1016/s0092-8674(04)00337-x

Cited by 198 publications

(174 citation statements)

References 64 publications

(1 reference statement)

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…Our results indicate that RAD51C and XRCC3 are the two most ancient RAD␤ gene clades in eukaryotes, supporting the idea that RAD51C and XRCC3 might be functionally more distinctive than other RAD␤ genes. Previous work suggested that RAD␤ subfamily proteins may have functions other than repair of double-strand breaks, such as repair of stalled replication forks during DNA synthesis (38) and telomere maintenance (39). It is reasonable to postulate that the evolution of multiple eukaryotic RAD␤ genes is driven by the need of efficient DNA repair and to maintain the integrity of complex genomes in eukaryotes (36).…”

Section: Discussionmentioning

confidence: 99%

Origins and evolution of the recA / RAD51 gene family: Evidence for ancient gene duplication and endosymbiotic gene transfer

Lin

Kong

Nei³

et al. 2006

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

254

283

View full text Add to dashboard Cite

The bacterial recA gene and its eukaryotic homolog RAD51 are important for DNA repair, homologous recombination, and genome stability. Members of the recA͞RAD51 family have functions that have differentiated during evolution. However, the evolutionary history and relationships of these members remains unclear. Homolog searches in prokaryotes and eukaryotes indicated that most eubacteria contain only one recA. However, many archaeal species have two recA͞RAD51 homologs (RADA and RADB), and eukaryotes possess multiple members (RAD51, RAD51B, RAD51C, RAD51D, DMC1, XRCC2, XRCC3, and recA). Phylogenetic analyses indicated that the recA͞RAD51 family can be divided into three subfamilies: (i) RAD␣, with highly conserved functions; (ii) RAD␤, with relatively divergent functions; and (iii) recA, functioning in eubacteria and eukaryotic organelles. The RAD␣ and RAD␤ subfamilies each contain archaeal and eukaryotic members, suggesting that a gene duplication occurred before the archaea͞eukaryote split. In the RAD␣ subfamily, eukaryotic RAD51 and DMC1 genes formed two separate monophyletic groups when archaeal RADA genes were used as an outgroup. This result suggests that another duplication event occurred in the early stage of eukaryotic evolution, producing the DMC1 clade with meiosisspecific genes. The RAD␤ subfamily has a basal archaeal clade and five eukaryotic clades, suggesting that four eukaryotic duplication events occurred before animals and plants diverged. The eukaryotic recA genes were detected in plants and protists and showed strikingly high levels of sequence similarity to recA genes from proteobacteria or cyanobacteria. These results suggest that endosymbiotic transfer of recA genes occurred from mitochondria and chloroplasts to nuclear genomes of ancestral eukaryotes.origins of meiosis and eukaryotes ͉ phylogenetic analysis ͉ recombination ͉ DNA repair ͉ organellar genes D NA double-strand breaks (DSBs) can occur either spontaneously during DNA replication or by exogenous DNAdamaging agents. Efficient repair of DSBs is critical for genomic stability and cellular viability (1). A major DSB repair pathway is homologous recombination, which is also critical for meiosis and generation of genetic diversity. Among the best known recombination genes are the Escherichia coli recA gene and its eukaryotic homologs RAD51s (2, 3). recA encodes a DNA-dependent ATPase that binds to single-stranded DNA and promotes strand invasion and exchange between homologous DNA molecules (4). The two eukaryotic recA homologs, RAD51 and DMC1, were first discovered in the budding yeast Saccharomyces cerevisiae and are structurally and functionally similar to the E. coli recA gene (5, 6).Homologs of recA and RAD51 have then been identified in many prokaryotes and eukaryotes. In eubacteria, only one recA gene has been previously reported in each species (7). Unlike eubacteria, several archaeal species have two recA͞RAD51-like genes, called RADA and RADB (Table 1, which is published as supporting information on the PNAS web site) (8, 9)....

show abstract

Section: Discussionmentioning

confidence: 99%

Origins and evolution of the recA / RAD51 gene family: Evidence for ancient gene duplication and endosymbiotic gene transfer

Lin

Kong

Nei³

et al. 2006

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

254

283

View full text Add to dashboard Cite

show abstract

“…The vectors expressing shRNA's against p53 (shp53) and GFP (shGFP, control) have been described previously (Grandori et al, 2003;Tarsounas et al, 2004). Phoenix cells (from ATCC) carrying the amphotropic receptor were used to generate retroviral supernatants.…”

Section: Rna Interference To Shut-down P53mentioning

confidence: 99%

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

2006

View full text Add to dashboard Cite

Among microtubule-targeting agents, docetaxel has received recent interest owing to its good therapeutic index. Clinical trials have underlined its potential for the treatment of advanced breast cancer, although little is known about its molecular mode of action in this context. We characterized the molecular changes induced by docetaxel in two well-known human breast carcinoma cell lines. Two mechanisms of action according to drug concentration were suggested by a biphasic sensitivity curve, and were further validated by cell morphology, cell cycle and cell death changes. Two to four nanomolar docetaxel induced aberrant mitosis followed by late necrosis, and 100 nM docetaxel induced mitotic arrest followed by apoptosis. Passing through mitosis phase was a requirement for hypodiploidy to occur, as shown by functional studies in synchronized cells and by combining docetaxel with the proteasome inhibitor MG132. Transcriptional profiling showed differences according to cell line and docetaxel concentration, with cell cycle, cell death and structural genes commonly regulated in both cell lines. Although p53 targets were mainly induced with low concentration of drug in MCF7 cells, its relevance in the dual mechanism of docetaxel cytotoxicity was ruled out by using an isogenic shp53 cell line. Many of the genes shown in this study may contribute to the dual mechanism by which docetaxel inhibits the growth of breast cancer cells at different concentrations. These findings provide a basis for rationally enhancing docetaxel therapy, considering lower concentrations, and better drug combinations.

show abstract

“…19,20 Phoenix cells (from ATCC) carrying the amphotropic receptor were used to generate retroviral supernatants. The retrovirus infection protocol is as previously described.…”

Section: Rna Interference To Shut-down P53mentioning

confidence: 99%

Transcriptional profiling of MCF7 breast cancer cells in response to 5‐Fluorouracil: Relationship with cell cycle changes and apoptosis, and identification of novel targets of p53

Hernández-Vargas

Ballestar

Carmona-Sáez

et al. 2006

Intl Journal of Cancer

View full text Add to dashboard Cite

The availability of oral precursors of 5-Fluorouracil (5-FU) and its favorable results in treating advanced breast cancer have renewed the interest in the molecular mechanisms underlying its cytotoxicity. We have compared the changes in cell cycle and cell death parameters induced by 2 different concentrations of 5-FU (IC50 and IC80) in the breast adenocarcinoma cell line MCF7. G1/S cell cycle arrest was associated with both concentrations, whereas cell death was mainly induced after IC80 5-FU. These changes were correlated with gene expression assessed by cDNA microarray analysis. Main findings included an overexpression of p53 target genes involved in cell cycle and apoptosis (CDKN1A/ p21, TP53INP, TNFRSF6/FAS and BBC3/PUMA), and significant repression of Myc. High dose 5-FU also induced a higher regulation of the mitochondrial death genes APAF1, BAK1 and BCL2, and induction of genes of the ID family. Furthermore, we establish a direct causal relationship between p21, ID1 and ID2 overexpression, increased acetylation of histones H3 and H4 and binding of p53 to their promoters as a result of 5-FU treatment. The relevance of these findings was further studied after interfering p53 expression in MCF7 cells (shp53 cells), showing a lower induction of both, ID1 and ID2 transcripts, after 5-FU when compared with MCF7 shGFP control cells. This molecular characterization of dose-and time-dependent modifications of gene expression after 5-FU treatment should provide a resource for future basic studies addressing the molecular mechanisms of chemotherapy in breast cancer. ' 2006 Wiley-Liss, Inc.Key words: 5-Fluorouracil; cDNA microarrays; p53; E2F1; ID proteins Carcinogenesis is a multistep process involving genetic and epigenetic alterations that drive the progressive transformation of normal cells into malignant types. Deregulated processes involved in tumorigenesis, such as regulation of cell cycle progression, angiogenesis and apoptosis, provide rational targets for novel therapies. For this reason, there is now more emphasis on understanding the mechanisms of carcinogenesis and how these can be exploited when designing new therapeutic agents. 1 Capecitabine is an example of a rationally designed cytotoxic treatment. It is designed to generate 5-Fluorouracil (5-FU) preferentially in tumor cells, by exploiting the higher activity of the activating enzyme thymidine phosphorylase in tumors compared with healthy tissues. Tumor-specific activation has the potential to increase intratumor drug levels to enhance efficacy and minimize toxicity. Proof of this principle is provided by clinical trial results, showing that capecitabine is effective and has a favorable safety profile in the treatment of metastatic breast cancer. 1 Capecitabine active metabolite, 5-FU, is one of the most widely used chemotherapy drugs for the treatment of solid tumors. However, despite its extensive use in clinical practice, only in recent years we have began to understand the molecular basis for 5-FU toxicity on cancer cells. As a pyrimidine ana...

show abstract

Telomere Maintenance Requires the RAD51D Recombination/Repair Protein

Cited by 198 publications

References 64 publications

Origins and evolution of the recA / RAD51 gene family: Evidence for ancient gene duplication and endosymbiotic gene transfer

Origins and evolution of the recA / RAD51 gene family: Evidence for ancient gene duplication and endosymbiotic gene transfer

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

Transcriptional profiling of MCF7 breast cancer cells in response to 5‐Fluorouracil: Relationship with cell cycle changes and apoptosis, and identification of novel targets of p53

Contact Info

Product

Resources

About