Sumoylation Inhibits the Growth Suppressive Properties of Ikaros

Apostolov, Apostol; Litim-Mecheri, Isma; Oravecz, Attila; Goepp, Marie; Kirstetter, Peggy; Marchal, Patricia; Ittel, Antoine; Mauvieux, Laurent; Chan, Susan; Kastner, Philippe

doi:10.1371/journal.pone.0157767

Cited by 14 publications

(7 citation statements)

References 31 publications

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“…Consistent with this increased binding to DNA, IKZF1 R183H/C expression resulted in hyperrepression of the HES1 and MCL1 promoter activities and the hyperactivation of the MSH2 promoter activity (when compared with IKZF1 WT ), which are known targets of IKZF1 (Fig. 2E) (16,17). In contrast, expression of IKZF1 N159S and IKZF1 R162Q had no effect as expected for loss-of-function variants.…”

Section: Of 14supporting

confidence: 67%

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

et al. 2022

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IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline IKZF1 haploinsufficient ( IKZF1 HI ) and dominant-negative ( IKZF1 DN ) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous IKZF1 variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T H ) skewing toward T H 2, low numbers of regulatory T cells (T reg ), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1 HI and IKZF1 DN , IKZF1 R183H/C proteins showed increased DNA binding associated with increased gene expression of T H 2 and PC differentiation, thus demonstrating that IKZF1 R183H/C behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T H 2 and PC abnormalities caused by IKZF1 R183H/C . These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.

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Section: Of 14supporting

confidence: 67%

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

et al. 2022

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“…Key to this model is that sumoylation takes place only after Sko1 has bound DNA, which is supported by our finding that DNA binding mutations eliminate Sko1 sumoylation. Similarly, DNA binding mutations have been shown to prevent sumoylation of other TFs such as Gcn4 and Ikaros, as well as non-TF DNA-binding proteins, including yeast Yku70, human TDG and viral ULFF, which are involved in DNA damage repair [28,65,66]. This suggests that the sumoylation apparatus can distinguish between DNA-bound and unbound forms of many chromatin-associated proteins, possibly as a result of conformational changes that may occur after binding DNA, or due to the proximity of the sumoylation machinery with chromatin.…”

Section: Discussionmentioning

confidence: 99%

Sumoylation of DNA-bound transcription factor Sko1 prevents its association with nontarget promoters

2019

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Sequence-specific transcription factors (TFs) represent one of the largest groups of proteins that is targeted for SUMO post-translational modification, in both yeast and humans. SUMO modification can have diverse effects, but recent studies showed that sumoylation reduces the interaction of multiple TFs with DNA in living cells. Whether this relates to a general role for sumoylation in TF binding site selection, however, has not been fully explored because few genome-wide studies aimed at studying such a role have been reported. To address this, we used genome-wide analysis to examine how sumoylation regulates Sko1, a yeast bZIP TF with hundreds of known binding sites. We find that Sko1 is sumoylated at Lys 567 and, although many of its targets are osmoresponse genes, the level of Sko1 sumoylation is not stress-regulated and the modification does not depend or impinge on its phosphorylation by the osmostress kinase Hog1. We show that Sko1 mutants that cannot bind DNA are not sumoylated, but attaching a heterologous DNA binding domain restores the modification, implicating DNA binding as a major determinant for Sko1 sumoylation. Genome-wide chromatin immunoprecipitation (ChIP-seq) analysis shows that a sumoylation-deficient Sko1 mutant displays increased occupancy levels at its numerous binding sites, which inhibits the recruitment of the Hog1 kinase to some induced osmostress genes. This strongly supports a general role for sumoylation in reducing the association of TFs with chromatin. Extending this result, remarkably, sumoylation-deficient Sko1 binds numerous additional promoters that are not normally regulated by Sko1 but contain sequences that resemble the Sko1 binding motif. Our study points to an important role for sumoylation in modulating the interaction of a DNA-bound TF with chromatin to increase the specificity of TF-DNA interactions.

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“… 39-41 Sumoylation of the hematopoiesis-associated TF Ikaros was shown to depend on its intact DNA-binding domain, suggesting that SUMO regulates Ikaros function specifically after it binds to its chromatin targets. 42 A number of groups have used ChIP in yeast or mammalian cells to show that Ubc9 and sumoylated proteins are detected specifically near promoters or transcriptional start sites of actively transcribed RNAP II-dependent genes, which implies that sumoylation plays a general role in regulating TFs during active transcription. 43-47 For the most part, the specific function of SUMO at these transcriptionally active chromatin sites is unknown, and whether sumoylation affects occupancy of TFs while bound to DNA during active transcription has not been examined.…”

Section: Association With and Availability To Bind Chromatinmentioning

confidence: 99%

Regulation of transcription factors by sumoylation

et al. 2017

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Transcription factors (TFs) are among the most frequently detected targets of sumoylation, and effects of the modification have been studied for about 200 individual TFs to date. TF sumoylation is most often associated with reduced target gene expression, which can be mediated by enhanced interactions with corepressors or by interference with protein modifications that promote transcription. However, recent studies show that sumoylation also regulates gene expression by controlling the levels of TFs that are associated with chromatin. SUMO can mediate this by modulating TF DNA-binding activity, promoting clearance of TFs from chromatin, or indirectly, by influencing TF abundance or localization.

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Sumoylation Inhibits the Growth Suppressive Properties of Ikaros

Cited by 14 publications

References 31 publications

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Sumoylation of DNA-bound transcription factor Sko1 prevents its association with nontarget promoters

Regulation of transcription factors by sumoylation

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