Reverse Transcriptase Activity in Mature Spermatozoa of Mouse

Giordano, Roberto; Magnano, Anna Rosa; Zaccagnini, Germana; Pittoggi, Carmine; Moscufo, Nicola; Lorenzini, R; Spadafora, Corrado

doi:10.1083/jcb.148.6.1107

Cited by 104 publications

(78 citation statements)

References 28 publications

(36 reference statements)

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“…Although there are few direct examples, genetic evidence from yeast are consistent with cDNAs being an intermediate in recombination (Derr and Strathern 1993). More directly, RNA injected into mouse (Giordano et al 2000) has been shown to yield cDNA. If the cDNA interacted with complementary displaced single-strand flaps that arise during normal DNA replication, this would result in stabilized double-stranded flaps that would be resistant to cleavage by the Fen1 flap-processing enzyme and a stabilized inverted repeat in the lagging strand .…”

Section: Genome Research 21mentioning

confidence: 88%

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Stenger

Lobachev²,

Gordenin³

et al. 2001

Genome Res.

117

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Alu sequences, the most abundant class of large dispersed DNA repeats in human chromosomes, contribute to human genome dynamics. Recently we reported that long inverted repeats, including human Alus, can be strong initiators of genetic change in yeast. We proposed that the potential for interactions between adjacent, closely related Alus would influence their stability and this would be reflected in their distribution. We have undertaken an extensive computational analysis of all Alus (the database is at http://dir.niehs.nih.gov/ALU) to better understand their distribution and circumstances under which Alu sequences might affect genome stability. Alus separated by <650 bp were categorized according to orientation, length of regions sharing high sequence identity, distance between highly identical regions, and extent of sequence identity. Nearly 50% of all Alu pairs have long alignable regions (>275 bp), corresponding to nearly full-length Alus, regardless of orientation. There are dramatic differences in the distributions and character of Alu pairs with closely spaced, nearly identical regions. For Alu pairs that are directly repetitive, ∼30% have highly identical regions separated by <20 bp, but only when the alignments correspond to near full-size or half-size Alus. The opposite is found for the distribution of inverted repeats: Alu pairs with aligned regions separated by <20 bp are rare. Furthermore, closely spaced direct and inverted Alus differ in their truncation patterns, suggesting differences in the mechanisms of insertion. At larger distances, the direct and inverted Alu pairs have similar distributions. We propose that sequence identity, orientation, and distance are important factors determining insertion of adjacent Alus, the frequency and spectrum of Alu-associated changes in the genome, and the contribution of Alu pairs to genome instability. Based on results in model systems and the present analysis, closely spaced inverted Alu pairs with long regions of alignment are likely at-risk motifs (ARMs) for genome instability.

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Section: Genome Research 21mentioning

confidence: 88%

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Stenger

Lobachev²,

Gordenin³

et al. 2001

Genome Res.

117

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“…Murine spermatozoa are also endowed with a functional RT activity, able to retrotranscribe exogenous RNA molecules into cDNA copies that can then be delivered to embryos during fertilization (Giordano et al, 2000). A similar RT activity is present in mouse cleavage embryos (CP, IS, EM, RL and CS, submitted).…”

Section: Introductionmentioning

confidence: 97%

Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation

et al. 2003

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Endogenous, nontelomeric reverse transcriptase (RT) is encoded by two classes of repeated elements: retrotransposons and endogenous retroviruses. Expression of RT-coding genes is generally repressed in differentiated nonpathological tissues, yet is active in the mammalian germ line, embryonic tissues and tumor cells. Nevirapine is a non-nucleoside RT inhibitor with a well-characterized inhibitory activity on RT enzymes of retroviral origin. Here, we show that nevirapine is also an effective inhibitor of the endogenous RT in murine and human cell lines. In addition, progenitor and transformed cells undergo a significant reduction in the rate of cell growth upon exposure to nevirapine. This is accompanied by the onset of differentiation, as depicted in F9 and C2C7 progenitor cells cultures in which nevirapine triggers the expression of differentiation-specific markers. Consistent with this, an extensive reprogramming of cell cycle gene expression was depicted in nevirapine-treated F9 cultures. Furthermore, nevirapine exposure rescued the differentiation block present in acute myeloid leukemia (AML) cell lines and primary blasts from two AML patients, as indicated by morphological, functional and immunophenotypic assays. The finding that an RT inhibitor can modulate cell proliferation and differentiation suggests that RT may represent a novel target in the development of therapeutical approaches to neoplasia.

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“…More recently, the realization that retrotransposons can reshape the genome and contribute to modulation of gene expression has led to reconsider that hypothesis. Growing evidence indicate that RTcoding genes are expressed at low levels, if at all, in differentiated nonpathological tissues; in contrast, high expression is distinctive of germ cells (Kiessling et al, 1989;Giordano et al, 2000), embryos (Poznanski and Calarco, 1991;Packer et al, 1993), embryonic tissues (Mwenda, 1993), and undifferentiated and transformed cells (Deragon et al, 1990;Martin, 1991;Martin and Branciforte, 1993), suggesting that levels of RT expression are linked to the proliferative potential of the cell. In addition, RT gene activity is upregulated by a variety of stimuli acting at the genome-wide level, for example, cellular stress (Hagan et al, 2003), heat shock, cycloheximide, adenovirus infection (Li and Schmid, 2001), genotoxic agents (Hagan and Rudin, 2002), and DNA base analogs (Khan et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth

et al. 2005

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Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy.

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Reverse Transcriptase Activity in Mature Spermatozoa of Mouse

Cited by 104 publications

References 28 publications

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth

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