Induction of long interspersed nucleotide element-1 (L1) retrotransposition by 6-formylindolo[3,2-
            <i>b</i>
            ]carbazole (FICZ), a tryptophan photoproduct

Okudaira, Noriyuki; Iijima, Kenta; Koyama, Tsutomu; Minemoto, Yuzuru; Kano, Shigeyuki; Mimori, A; Ishizaka, Yukihito

doi:10.1073/pnas.1001252107

Cited by 42 publications

(99 citation statements)

References 41 publications

(40 reference statements)

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“…First, we found that 6-formylindolo [3,2-b]carbazole (FICZ), a tryptophan photoproduct, induced L1-RTP (37). FICZ is highly active, and even picomolar comncentratiom of the compound induced L1-RTP.…”

Section: Induction Of L1-rtp By An Environmental Compound and Identifmentioning

confidence: 99%

Regulation of Retrotransposition of Long Interspersed Element-1 by Mitogen-Activated Protein Kinases

Ishizaka¹,

Okudaira²,

Okamura³

2012

Protein Kinases

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Protein Kinases 188 Biology of L1-RTPL1, a non-long terminal repeat (non-LTR)-type endogenous retroelement, encodes two proteins: open reading frames 1 and 2 (ORF1 and 2) (3). ORF1 is a cytoplasmic 40 kDa protein that is present within ribonucleoprotein complexes (21-23). ORF1 associates in cis with L1-mRNA (24) and functions as a chaperone of L1-mRNA (25). ORF2 is a protein of about 150 kDa with dual activities as reverse transcriptase (RT) (26) and an endonuclease (27). ORF2 recognizes the 5′-TTAAAA hexanucleotide in the genome and induces a nick between 3′-AA and TTTT in the complementary strand (28,29). It has been proposed that the first-strand DNA is synthesized by target site-primed reverse transcription (3,29). ORF1 and 2 complete the entire process of L1-RTP and are competent for the induction of retrotransposition of Alu, a non-autonomous retroelements (30, 31). Reported triggers of L1-RTPAs to the environmental factors that induce L1-RTP in somatic cells, Farkash et al. reported that gamma irradiation at 4.5 Gy induced L1-RTP (32). Independently, Deiniger's group reported that heavy metals of such as mercury, cadmium and nickel also induced L1-RTP (33,34). They also reported that nickel-induced L1-RTP is induced by a post-transcriptional mechanism (34). As to an environmental carcinogen, Stribinskis and Ramos found that benzo[a]pyrene (B[a]P) induced L1-RTP (35). An extensive analysis revealed that aryl hydrocarbon receptor (AhR), which serves as a receptor for such environmental pollutants as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (36), was required for the B[a]P-induced L1-RTP (35). Because TCDD, a non-genotoxic hydrocarbon carcinogen, did not induce L1-RTP, it was proposed that as one of the its mechanisms an AhR-dependent cellular response converts B[a]P into an active genotoxic compound, which in turn induces L1-RTP (35). Although the exact modes of L1-RTP are unclear, these studies inspired us to investigate the possibility that various environmental compounds can induce L1-RTP.

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Section: Induction Of L1-rtp By An Environmental Compound and Identifmentioning

confidence: 99%

Regulation of Retrotransposition of Long Interspersed Element-1 by Mitogen-Activated Protein Kinases

Ishizaka¹,

Okudaira²,

Okamura³

2012

Protein Kinases

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“…Recent studies have shown that phosphorylation-related proteins can be coimmunoprecipitated with ORF1p or L1 RNPs (39,40). In addition, the mitogen-activated protein kinase (MAPK) p38 has been implicated in L1 activation by environmental toxins (41,42), and its expression can be increased by exogenous ORF1p (43). Although large-scale proteomic studies can only identify a subset of phospho sites (44), a phosphoproteomic study of human embryonal stem cells, in which L1 is active, identified an ORF1p fragment phosphorylated on S18 (45).…”

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confidence: 99%

Phosphorylation of ORF1p is required for L1 retrotransposition

Cook

Jones

Furano

2015

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

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Although members of the L1 (LINE-1) clade of non-LTR retrotransposons can be deleterious, the L1 clade has remained active in most mammals for ∼100 million years and generated almost 40% of the human genome. The details of L1-host interaction are largely unknown, however. Here we report that L1 activity requires phosphorylation of the protein encoded by the L1 ORF1 (ORF1p). Critical phospho-acceptor residues (two serines and two threonines) reside in four conserved proline-directed protein kinase (PDPK) target sites. The PDPK family includes mitogen-activated protein kinases and cyclin-dependent kinases. Mutation of any PDPK phospho-acceptor inhibits L1 retrotransposition. The phosphomimetic aspartic acid can restore activity at the two serine sites, but not at either threonine site, where it is strongly inhibitory. ORF1p also contains conserved PDPK docking sites, which promote specific interaction of PDPKs with their targets. As expected, mutations in these sites also inhibit L1 activity. PDPK mutations in ORF1p that inactivate L1 have no significant effect on the ability of ORF1p to anneal RNA in vitro, an important biochemical property of the protein. We show that phosphorylated PDPK sites in ORF1p are required for an interaction with the peptidyl prolyl isomerase 1 (Pin1), a critical component of PDPK-mediated regulation. Pin1 acts via isomerization of proline side chains at phosphorylated PDPK motifs, thereby affecting substrate conformation and activity. Our demonstration that L1 activity is dependent on and integrated with cellular phosphorylation regulatory cascades significantly increases our understanding of interactions between L1 and its host.L 1 (or LINE-1) activity over the last ∼100 million years of primate evolution has generated ∼40% of the human genome (1, 2); thus, succeeding families of L1 elements are the main drivers of genetic expansion. These autonomously replicating elements convert their RNA transcripts and those of other genetic elements, particularly SINEs, into genomic DNA (3). A generic L1 element is 6-7 kb and contains the following: a 5′ UTR; ORF1, which encodes the coiled-coil mediated trimeric nucleic acid chaperone protein ORF1p; ORF2, which encodes a DNA endonuclease and reverse-transcriptase ORF2p; and a 3′ UTR terminated in a polyA sequence (reviewed in refs. 3 and 4). ORF1p, ORF2p, and L1 RNA form ribonucleoprotein particles (RNPs) that are likely intermediates in L1 retrotransposition (5-8). The L1-encoded proteins ORF1p and ORF2p are essential in cell culture-based retrotransposition assays (9) and in vitro assays using RNPs from cells transfected with L1 retrotransposition vectors (7). Although the role of ORF1p in retrotransposition is not known, mutations that affect its nucleic acid binding and chaperone activities can inactivate L1 (7, 9, 10).L1 activity can damage DNA (11), can generate genetic diversity and rearrangements (12-16), and is activated in certain tumors (17-19) and other somatic cells (20), including neuronal cells (21-23). Despite being deleterious (2...

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“…FICZ also is bound to the AHR with the highest affinity known to date and thereby demonstrates the characteristics of an endogenous signaling molecule; i.e., it stimulates an efficient receptor-mediated pathway for transcriptional activation of metabolic enzymes that, among other things, catalyze the clearance of FICZ itself, thereby generating negative feedback regulation of its action (3,26,27). The physiological effects of FICZ reported to date include alterations in circadian rhythms (28), adaptive responses to UV light (4,29), induced retrotransposition of long interspersed nucleotide element-1 (30), and stimulated production of IL-22, a member of the IL-10 cytokine family that helps regulate inflammatory responses associated with many autoimmune diseases (17,18,31). In humans, the involvement of FICZ in IL-22 production has been demonstrated both in stimulated blood cells from the umbilical cord (32) and in intestinal tissue from patients with inflammatory bowel disease (31).…”

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Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

Wincent

Bengtsson²,

Bardbori³

et al. 2012

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

185

215

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Altered systemic levels of 6-formylindolo [3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro-and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3′-methoxy-4′-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.

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Induction of long interspersed nucleotide element-1 (L1) retrotransposition by 6-formylindolo[3,2- b ]carbazole (FICZ), a tryptophan photoproduct

Cited by 42 publications

References 41 publications

Regulation of Retrotransposition of Long Interspersed Element-1 by Mitogen-Activated Protein Kinases

Regulation of Retrotransposition of Long Interspersed Element-1 by Mitogen-Activated Protein Kinases

Phosphorylation of ORF1p is required for L1 retrotransposition

Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

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