A case of cryocrystalglobulinemia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133638/1/trf13528_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133638/2/trf13528.pd

DNA Damage and L1 Retrotransposition

Barbara McClintock was the first to suggest that transposons are a source of genome instability and that genotoxic stress assisted in their mobilization. The generation of double-stranded DNA breaks (DSBs) is a severe form of genotoxic stress that threatens the integrity of the genome, activates cell cycle checkpoints, and, in some cases, causes cell death. Applying McClintock's stress hypothesis to humans, are L1 retrotransposons, the most active autonomous mobile elements in the modern day human genome, mobilized by DSBs? Here, evidence that transposable elements, particularly retrotransposons, are mobilized by genotoxic stress is reviewed. In the setting of DSB formation, L1 mobility may be affected by changes in the substrate for L1 integration, the DNA repair machinery, or the L1 element itself. The review concludes with a discussion of the potential consequences of L1 mobilization in the setting of genotoxic stress

Gamma radiation increases endonuclease-dependent L1 retrotransposition in a cultured cell assay

Long Interspersed Elements (LINE-1s, L1s) are the most active mobile elements in the human genome and account for a significant fraction of its mass. The propagation of L1 in the human genome requires disruption and repair of DNA at the site of integration. As Barbara McClintock first hypothesized, genotoxic stress may contribute to the mobilization of transposable elements, and conversely, element mobility may contribute to genotoxic stress. We tested the ability of genotoxic agents to increase L1 retrotransposition in a cultured cell assay. We observed that cells exposed to gamma radiation exhibited increased levels of L1 retrotransposition. The L1 retrotransposition frequency was proportional to the number of phosphorylated H2AX foci, an indicator of genotoxic stress. To explore the role of the L1 endonuclease in this context, endonuclease-deficient tagged L1 constructs were produced and tested for their activity in irradiated cells. The activity of the endonuclease-deficient L1 was very low in irradiated cells, suggesting that most L1 insertions in irradiated cells still use the L1 endonuclease. Consistent with this interpretation, DNA sequences that flank L1 insertions in irradiated cells harbored target site duplications. These results suggest that increased L1 retrotransposition in irradiated cells is endonuclease dependent. The mobilization of L1 in irradiated cells potentially contributes to genomic instability and could be a driving force for secondary mutations in patients undergoing radiation therapy

Inhibition of EZH2 Ameliorates Lupusâ Like Disease in MRL/lpr Mice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151823/1/art40931_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151823/2/art40931.pd

Factors at de novo donorâ specific antibody initial detection associated with allograft loss: a multicenter study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149234/1/tri13395-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149234/2/tri13395_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149234/3/tri13395.pd

Keeping L1s in line: Genomic defenses against retrotransposition

Long Interspersed Elements (L1) are mobile elements responsible for shaping as much as 45% of the human genome. Highly active L1 retrotransposons are agents of genomic instability in vivo. Conversely, L1s might be activated by genomic stress. Here I report on one form of DNA damage, gamma radiation, which is able to increase the retrotransposition frequency of a tagged L1 in tissue culture. Gamma radiation likely enhances L1 mobility by inducing a more favorable cellular environment for endonuclease-dependent retrotransposition. Because L1 mobility is toxic to cells, the survival of an organism may be contingent on its ability to regulate L1 elements. One strategy of L1 regulation is to limit the cell types in which it is active; namely, by restricting L1 expression and retrotransposition to germ cells. New L1 insertions also appear to be subject to regulation. CpG methylation appears to play a role in establishing tissue specific silencing of L1 insertions. L1 insertions are differentially methylated in somatic and germ tissues. Moreover, new L1 insertions are not downregulated in cells grown in tissue culture under demethylating conditions. However, maintenance of L1 repression is likely to involve multiple pathways, as even a toxic dose of demethylating agents is not sufficient to re-express a silenced L1 insertion. DNA methylation is likely to be an important weapon in a cell's arsenal to defend the integrity of the genome against assault by mobile elements

Vascularized plexus allotransplantation: a new hope in brachial plexus palsy?

No abstract available