Parole terms for a killer

Larsen, Brian D.; Megeney, Lynn A.

doi:10.4161/cc.9.15.12335

Cited by 17 publications

(8 citation statements)

References 49 publications

(58 reference statements)

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“…Irrespective of the precise molecular mechanism behind the RAG-endowed cellular fitness of lymphocytes, it is fascinating to envision a paradigm where a programmed DNA endonuclease like RAG is able to stably “imprint” the functional properties of a developmental lineage long after it has acted on it. Our findings identify a novel role for the RAG proteins and add to a growing body of evidence implicating “controlled” DNA damage in the regulation of gene expression, cell development, and cell fate in eukaryotes (Abramson et al, 2010; Bredemeyer et al, 2008; Ju et al, 2006; Larsen and Megeney, 2010; Larsen et al, 2010; Schroeder et al, 2013). …”

Section: Discussionsupporting

confidence: 57%

The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells

Karo

Schatz

Sun

2014

Cell

152

182

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SUMMARY The emergence of the recombination activating genes (RAG) in jawed vertebrates endowed adaptive immune cells with the ability to assemble a diverse set of antigen receptor genes. In contrast, innate lymphocytes such as natural killer (NK) cells are not believed to require RAG. Here, we report that select subsets of NK cells unable to express RAG or RAG endonuclease activity during ontogeny exhibit cell-intrinsic hyper-responsiveness but diminished capacity to survive following virus-driven proliferation. This deficit in cell survival may stem in part from reduced expression of DNA damage response mediators and defects in the repair of DNA breaks. Evidence for this novel function of RAG was also observed in T cells and innate lymphoid cells (ILC), revealing an unexpected role for the RAG proteins beyond V(D)J recombination. We propose that DNA cleavage events mediated by RAG endow developing adaptive and innate lymphocytes with a cellular “fitness” that safeguards their persistence later in life during episodes of rapid proliferation or cellular stress.

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Section: Discussionsupporting

confidence: 57%

The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells

Karo

Schatz

Sun

2014

Cell

152

182

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“…Caspase signal transduction is considered irreversible or long-lasting due to their proteolytic activity [48]. Among their many targets [49], several key cell cycle regulators [50–52] and cytoskeletal components [53] have been identified, and caspases can even induce expression of specific genes [42, 54]. Therefore, caspases are suitable candidates to manipulate the cytoskeletal architecture and rearrange the cytoplasm in complex processes such as cell reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Fgf regulates dedifferentiation during skeletal muscle regeneration in adult zebrafish

Saera-Vila

Kish

Kahana

2016

Cellular Signalling

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Fibroblast growth factors (Fgfs) regulate critical biological processes such as embryonic development, tissue homeostais, wound healing, and tissue regeneration. In zebrafish, Fgf signaling plays an important role in the regeneration of the spinal cord, liver, heart, fin, and photoreceptors, although its exact mechanism of action is not fully understood. Utilizing an adult zebrafish extraocular muscle (EOM) regeneration model, we demonstrate that blocking Fgf receptor function using either a chemical inhibitor (SU5402) or a dominant-negative transgenic construct (dnFGFR1a:EGFP) impairs muscle regeneration. Adult zebrafish EOMs regenerate through a myocyte dedifferentiation process, which involves a muscle-to-mesenchyme transition and cell cycle reentry by differentiated myocytes. Blocking Fgf signaling reduced cell proliferation and active caspase 3 levels in the regenerating muscle with no detectable levels of apoptosis, supporting the hypothesis that Fgf signaling is involved in the early steps of dedifferentiation. Fgf signaling in regenerating myocytes involves the Mapk/Erk pathway: inhibition of Mek activity with U0126 mimicked the phenotype of the Fgf receptor inhibition on both muscle regeneration and cell proliferation, and activated ERK (p-ERK) was detected in injured muscles by immunofluorescence and western blot. Interestingly, following injury, ERK2 expression is specifically induced and activated by phosphorylation, suggesting a key role in muscle regeneration. We conclude that the critical early steps of myocyte dedifferentiation in EOM regeneration are dependent on Fgf signaling.

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“…More recently, DNA strand breakage has been demonstrated to exert a profound effect on cell fate, acting to limit stem cell self-renewal and stimulate differentiation, without a concomitant increase in cell death [ 11–19 ]. In the skeletal muscle lineage, cell differentiation is dependent upon a temporal activation of the caspase 3 protease and its cognate DNase CAD (caspase-activated DNase), which act to enhance muscle gene expression through targeted DNA strand breaks [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Temporal activation of XRCC1-mediated DNA repair is essential for muscle differentiation

et al. 2016

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Transient DNA strand break formation has been identified as an effective means to enhance gene expression in living cells. In the muscle lineage, cell differentiation is contingent upon the induction of caspase-mediated DNA strand breaks, which act to establish the terminal gene expression program. This coordinated DNA nicking is rapidly resolved, suggesting that myoblasts may deploy DNA repair machinery to stabilize the genome and entrench the differentiated phenotype. Here, we identify the base excision repair pathway component XRCC1 as an indispensable mediator of muscle differentiation. Caspase-triggered XRCC1 repair foci form rapidly within differentiating myonuclei, and then dissipate as the maturation program proceeds. Skeletal myoblast deletion of Xrcc1 does not have an impact on cell growth, yet leads to perinatal lethality, with sustained DNA damage and impaired myofiber development. Together, these results demonstrate that XRCC1 manages a temporally responsive DNA repair process to advance the muscle differentiation program.

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Parole terms for a killer

Cited by 17 publications

References 49 publications

The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells

The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells

Fgf regulates dedifferentiation during skeletal muscle regeneration in adult zebrafish

Temporal activation of XRCC1-mediated DNA repair is essential for muscle differentiation

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