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Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting.

ABSTRACT: Posttranslational modifications of nuclear proteins, including transcription factors, nuclear receptors, and their coregulators, have attracted much attention in cancer research. Although phosphorylation of oligodendrocyte transcription factor 2 (Olig2) may contribute to the notorious resistance of gliomas to radiation and genotoxic drugs, the precise mechanisms remain elusive. We show here that in addition to phosphorylation, Olig2 is also conjugated by small ubiquitin-like modifier-1 (SUMO1) at three lysine residues K27, K76, and K112. SUMOylation is required for Olig2 to suppress p53-mediated cell cycle arrest and apoptosis induced by genotoxic damage, and to enhance resistance to temozolomide (TMZ) in glioma. Both SUMOylation and triple serine motif (TSM) phosphorylation of Olig2 are required for the antiapoptotic function. Olig2 SUMOylation enhances its genetic targeting ability, which in turn occludes p53 recruitment to Cdkn1a promoter for DNA-damage responses. Our work uncovers a SUMOylation-dependent regulatory mechanism of Olig2 in regulating cancer survival.

SUBMITTER: Liu H

PROVIDER: S-EPMC7560653 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting.

Liu Huiqing H Weng Weiji W Guo Rongjun R Zhou Jie J Xue Jun J Zhong Shan S Cheng Jinke J Zhu Michael X MX Pan Si-Jian SJ Li Yong Y

Cell death and differentiation 20200601 11

Posttranslational modifications of nuclear proteins, including transcription factors, nuclear receptors, and their coregulators, have attracted much attention in cancer research. Although phosphorylation of oligodendrocyte transcription factor 2 (Olig2) may contribute to the notorious resistance of gliomas to radiation and genotoxic drugs, the precise mechanisms remain elusive. We show here that in addition to phosphorylation, Olig2 is also conjugated by small ubiquitin-like modifier-1 (SUMO1) a ...[more]

PMID: 32483381

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Project description:Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

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Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting.

Publications

Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting.

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