P53 suppresses SENP3 phosphorylation to mediate G2 checkpoint

Wang, Yang; Tian, Jing; Huang, Chao; Ma, Jiao; Hu, Gaolei; Chen, Yalan; Wang, Tianshi; Cai, Rong; Zuo, Yongchun; Tan, Hongsheng; Fan, Qiuju; Dong, Baijun; Xue, Wei; Yi, Jing; Chen, Guoqiang; Tang, Jun; Cheng, Jinke

doi:10.1038/s41421-020-0154-2

Cited by 16 publications

(14 citation statements)

References 40 publications

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“…[47][48][49][50] The p53induced cell cycle arrest may occur at either G 2 /M or G 1 /S checkpoints, reflecting cell context-specific outcomes in different cells. 47,50,51 Here, we found that Anp32b deletion in HSCs increased quiescent cells and impaired division and proliferation, whereas Anp32b deficiency in LSCs decreased quiescent cells and promoted their cell cycle entry, which was followed by enhanced proliferation and increased apoptosis, supporting that p53 plays different roles in fate decision of HSCs and LSCs as reviewed. 52 Principally, p53 promotes quiescence of HSCs, and the absence of p53 promotes HSC more cell cycle entry, whereas p53 preferentially induces apoptosis of LSCs, [13][14][15][16] although precise function of p53 on LSCs has not been clarified.…”

Section: Discussionsupporting

confidence: 60%

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

Yang

Zhu

Zhang³

et al. 2021

Blood

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Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and post-injury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from chronic myelogenous leukemia (CML) patients. Anp32b deletion enhances p53 transcriptional activity to impair LSCs function in a murine CML model, and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B, and identify ANP32B as a potential therapeutic target in treating CML.

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Section: Discussionsupporting

confidence: 60%

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

Yang

Zhu

Zhang³

et al. 2021

Blood

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“…Notably, the SUMOylation levels of the proteins are varied in response to mitochondrial stress [24]. As SUMO deconjugation proteases, SENPs have been considered to be the regulators of SUMOylation upon cellular stresses [25][26][27][28].…”

Section: Sumoylation Is a Stress-induced Processmentioning

confidence: 99%

SUMOylation-Mediated Response to Mitochondrial Stress

Cheng

Wang

2020

IJMS

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Mitochondrial stress is considered as a factor that reprograms the mitochondrial biogenesis and metabolism. As known, SUMOylation occurs through a series of stress-induced biochemical reactions. During the process of SUMOylation, the small ubiquitin-like modifier (SUMO) and its specific proteases (SENPs) are key signal molecules. Furthermore, they are considered as novel mitochondrial stress sensors that respond to the signals produced by various stresses. The responses are critical for mitochondrial homeostasis. The scope of this review is to provide an overview of the function of SUMOylation in the mitochondrial stress response, to delineate a SUMOylation-involved signal network diagram, and to highlight a number of key questions that remain answered.

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“…The C-terminal phosphorylation of yeast SUMO isopeptidase Ulp2 during mitosis may inhibit its isopeptidase activity (Baldwin et al, 2009). Cdk1mediated Ser/Thr phosphorylation in the N-terminal region of SENP3 in mitotic cells downregulates its deconjugation activity towards topoisomerase TopoIIa through decreasing its interaction with it (Wang et al, 2020;Wei et al, 2018). Different from the above Ser/Thr phosphorylation of SENPs, our study has demonstrated for the first time that in TCR signaling, Lckmediated tyrosine phosphorylation at SENP1 Y270 regulates the binding propensity between SENP1 and the SUMOconjugated substrate and then increases SENP1 isopeptidase activity, while blocking the endopeptidase activity towards pre-SUMO3 but not pre-SUMO1 and in turn enhancing SENP1 peptidase specificity.…”

Section: Discussionmentioning

confidence: 99%

TCR-Induced Tyrosine Phosphorylation at Tyr270 of SUMO Protease SENP1 by Lck Modulates SENP1 Enzyme Activity and Specificity

Cen

Gong

et al. 2022

Front. Cell Dev. Biol.

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Small ubiquitin-like modifier (SUMO) modification plays an important regulatory role in T cell receptor (TCR) signaling transduction. SUMO-specific proteases (SENPs) have dual-enzyme activities; they can both process SUMO precursors as endopeptidases and participate in SUMO deconjugation as isopeptidases. It remains unclear how the SUMO system, especially SENP1, is regulated by TCR signaling. Here, we show that Lck phosphorylates tyrosine 270 (Y270) of SENP1 upon TCR stimulation, indicating that SENP1 is a substrate of Lck. In vitro endopeptidase activity analysis showed that mutating SENP1 Y270 to either phenylalanine (F) to mimic the phosphorylation-defective state or to glutamate (E) to mimic the negative charge of tyrosine phosphorylation in the enzyme microenvironment did not change its endopeptidase activity towards pre-SUMO1. However, SENP1 Y270E but not Y270F mutation exhibited decreased endopeptidase activity towards pre-SUMO3. Through in vivo isopeptidase activity analysis by rescue expression of SENP1 and its Y270 mutants in a SENP1 CRISPR knockout T cell line, we found that SENP1 Y270F downregulated its isopeptidase activity towards both SUMO1 and SUMO2/3 conjugation by reducing SENP1 binding with sumoylated targets. While overexpression of SENP1 inhibited TCR-induced IL-2 production, overexpression of SENP1 Y270F enhanced it instead. In summary, TCR-induced Y270 phosphorylation of SENP1 may promote its isopeptidase activity and specifically decrease its endopeptidase activity against pre-SUMO3, which finely tunes activation of T cells.

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P53 suppresses SENP3 phosphorylation to mediate G2 checkpoint

Cited by 16 publications

References 40 publications

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

SUMOylation-Mediated Response to Mitochondrial Stress

TCR-Induced Tyrosine Phosphorylation at Tyr270 of SUMO Protease SENP1 by Lck Modulates SENP1 Enzyme Activity and Specificity

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