Etoposide Induces Nuclear Re-Localisation of AID

Lambert, Laurens J.; Walker, Simon; Feltham, Jack; Lee, Heather; Reik, Wolf; Houseley, Jonathan

doi:10.1371/journal.pone.0082110

Cited by 4 publications

(3 citation statements)

References 58 publications

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“…AID localizes to the nucleus in response to DNA damage induced by ionizing radiation and other agents [ 28 , 41 , 42 ]. This raised the possibility that AID nuclear pulses are a response to damage caused by DNA deamination catalyzed by nuclear AID present at levels too low to detect by imaging.…”

Section: Resultsmentioning

confidence: 99%

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Maizels

2019

PLoS Genet

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Activation-induced deaminase (AID) converts C to U and 5-methyl-C to T. These mutagenic activities are critical to immunoglobulin (Ig) gene diversification and epigenetic reprogramming, but they must be tightly controlled to prevent compromising cell fitness. AID acts in the nucleus but localizes predominately to the cytoplasm. To address this apparent paradox, we have carried out time-lapse imaging of AID in single living B cells and fibroblasts. We demonstrate that AID enters the nucleus in brief (30 min) pulses, evident in about 10% of cells in the course of a single cell cycle (24 hr imaging). Pulses do not depend on AID catalytic activity, but they are coordinated with nuclear accumulation of P53. Pulsing may protect cells from pathologic consequences of excess exposure to AID, or enable AID to synchronize its activity with transcription of genes that are AID targets or with nuclear entry of factors that act at sites of AID-catalyzed DNA deamination to promote Ig gene diversification or epigenetic reprogramming.

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Section: Resultsmentioning

confidence: 99%

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Maizels

2019

PLoS Genet

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“…Several groups have reported that treatments that cause DSBs (ionizing radiation, etoposide) can induce nuclear localization of AID [ 24 , 53 , 54 ]. A DSB-dependent signal may be relevant to CSR, but unlikely to be relevant to SHM.…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle Regulates Nuclear Stability of AID and Determines the Cellular Response to AID

Maizels

2015

PLoS Genet

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AID (Activation Induced Deaminase) deaminates cytosines in DNA to initiate immunoglobulin gene diversification and to reprogram CpG methylation in early development. AID is potentially highly mutagenic, and it causes genomic instability evident as translocations in B cell malignancies. Here we show that AID is cell cycle regulated. By high content screening microscopy, we demonstrate that AID undergoes nuclear degradation more slowly in G1 phase than in S or G2-M phase, and that mutations that affect regulatory phosphorylation or catalytic activity can alter AID stability and abundance. We directly test the role of cell cycle regulation by fusing AID to tags that destabilize nuclear protein outside of G1 or S-G2/M phases. We show that enforced nuclear localization of AID in G1 phase accelerates somatic hypermutation and class switch recombination, and is well-tolerated; while nuclear AID compromises viability in S-G2/M phase cells. We identify AID derivatives that accelerate somatic hypermutation with minimal impact on viability, which will be useful tools for engineering genes and proteins by iterative mutagenesis and selection. Our results further suggest that use of cell cycle tags to regulate nuclear stability may be generally applicable to studying DNA repair and to engineering the genome.

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“…Two previous studies have observed nuclear AID accumulation in adherent (non-B) cells upon induction of DNA strand breaks [ 42 ] or treatment with etoposide [ 43 ]. In both cases, nuclear AID accumulation affected only a minor proportion of the cells, in contrast to the substantial and homogenous AID accumulation we have observed in all the B cell lines used in this study.…”

Section: Discussionmentioning

confidence: 99%

PARP activation promotes nuclear AID accumulation in lymphoma cells

et al. 2016

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Activation-induced cytidine deaminase (AID) initiates immunoglobulin diversification in germinal center B cells by targeted introduction of DNA damage. As aberrant nuclear AID action contributes to the generation of B cell lymphoma, the protein's activity is tightly regulated, e.g. by nuclear/cytoplasmic shuttling and nuclear degradation. In the present study, we asked whether DNA damage may affect regulation of the AID protein. We show that exogenous DNA damage that mainly activates base excision repair leads to prevention of proteasomal degradation of AID and hence its nuclear accumulation. Inhibitor as well as knockout studies indicate that activation of poly (ADP-ribose) polymerase (PARP) by DNA damaging agents promotes both phenomena. These findings suggest that PARP inhibitors influence DNA damage dependent AID regulation, with interesting implications for the regulation of AID function and chemotherapy of lymphoma.

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Etoposide Induces Nuclear Re-Localisation of AID

Cited by 4 publications

References 58 publications

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Cell Cycle Regulates Nuclear Stability of AID and Determines the Cellular Response to AID

PARP activation promotes nuclear AID accumulation in lymphoma cells

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