REG-γ associates with and modulates the abundance of nuclear activation-induced deaminase

Uchimura, Yasuhiro; Barton, Lance F.; Rada, Cristina; Neuberger, Michael S.

doi:10.1084/jem.20110856

Cited by 66 publications

(58 citation statements)

References 27 publications

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“…7 Following that finding, more proteins, such as p21, ARF, p14, MAFA, and AID, were found to be degraded by REGγ. 8,30,43,44 Interestingly, REGγ can degrade oncoproteins including SRC-3 and PTTG1, as well as tumor suppressors including p21, ARF and p53. [7][8][9][10] Thus, it is expected that REGγ has a context-dependent role in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

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-Myc is a key transcriptional factor that has a prominent role in cell growth, differentiation and tumor development. Its protein levels are tightly controlled by ubiquitin-proteasome pathway and frequently deregulated in various cancers. Here, we report that the 11S proteasomal activator REGγ is a novel regulator of c-Myc abundance in cells. We showed that overexpression of wild-type REGγ, but not inactive mutants including N151Y and G250S, significantly promoted the degradation of c-Myc. Depletion of REGγ markedly increased the protein stability of c-Myc. REGγ interacts with the C-terminal region of c-Myc and regulates c-Myc protein turnover. Functionally, REGγ negatively regulates c-Myc-mediated cell proliferation. Interestingly, depletion of the Drosophila Reg homolog (dReg) in developing wings induced the upregulation of Drosophila Myc, which contributes to cell death. Collectively, these results suggest that REGγ proteasome has a conserved role in the regulation of Myc abundance in both mammalian cells and Drosophila.

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Section: Discussionmentioning

confidence: 99%

Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

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“…First, E58A does not prevent Zn ++ coordination (22). Second, it did not inhibit binding to DNA in electrophoretic mobility shift assays (Fig.…”

Section: Aid Variants With Enzymatic Activity-dependent Dominant-negamentioning

confidence: 91%

Activation induced deaminase C-terminal domain links DNA breaks to end protection and repair during class switch recombination

Zahn

Eranki

Patenaude

et al. 2014

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

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Activation-induced deaminase (AID) triggers antibody class switch recombination (CSR) in B cells by initiating DNA double strand breaks that are repaired by nonhomologous end-joining pathways. A role for AID at the repair step is unclear. We show that specific inactivation of the C-terminal AID domain encoded by exon 5 (E5) allows very efficient deamination of the AID target regions but greatly impacts the efficiency and quality of subsequent DNA repair. Specifically eliminating E5 not only precludes CSR but also, causes an atypical, enzymatic activity-dependent dominant-negative effect on CSR. Moreover, the E5 domain is required for the formation of AID-dependent Igh-cMyc chromosomal translocations. DNA breaks at the Igh switch regions induced by AID lacking E5 display defective end joining, failing to recruit DNA damage response factors and undergoing extensive end resection. These defects lead to nonproductive resolutions, such as rearrangements and homologous recombination that can antagonize CSR. Our results can explain the autosomal dominant inheritance of AID variants with truncated E5 in patients with hyper-IgM syndrome 2 and establish that AID, through the E5 domain, provides a link between DNA damage and repair during CSR.antibody gene diversification | isotype switching | somatic hypermutation

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“…Nuclear entry of AID depends on importin-3 and a conformational nuclear localization signal (NLS) at the C-terminus generated upon protein folding [37]. Ubiquitin-dependent and independent pathways target the vast majority of nuclear AID to proteasomes for degradation [38, 39] (Figure 2C). …”

Section: Regulation Of Aidmentioning

confidence: 99%

AID targeting: old mysteries and new challenges

Chandra

Bortnick

Murre

2015

Trends in Immunology

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Activation-induced cytidine deaminase (AID) mediates cytosine deamination and underlies two central processes in antibody diversification: somatic hypermutation and class-switch recombination. AID deamination is not exclusive to immunoglobulin loci; it can instigate DNA lesions in non-immunoglobulin genes and thus, stringent checks are in place to constrain and restrict its activity. Recent findings have provided new insights into the mechanisms that target AID activity to specific genomic regions, revealing an involvement for non-coding RNAs associated with polymerase pausing and with enhancer transcription as well as genomic architecture. We review these findings and integrate them into a model for multi-level regulation of AID expression and targeting in immunoglobulin and non-immunoglobulin loci. Within this framework we discuss gaps in understanding, and outline important areas of further research.

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REG-γ associates with and modulates the abundance of nuclear activation-induced deaminase

Abstract: REG-γ, a protein involved in protein degradation, binds to nuclear AID, and REG-γ–deficient B cells contain more AID and exhibit increased immunoglobulin class switching.

Cited by 66 publications

References 27 publications

Regulation of c-Myc protein stability by proteasome activator REGγ

Regulation of c-Myc protein stability by proteasome activator REGγ

Activation induced deaminase C-terminal domain links DNA breaks to end protection and repair during class switch recombination

AID targeting: old mysteries and new challenges

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