FATS is an E2-independent ubiquitin ligase that stabilizes p53 and promotes its activation in response to DNA damage

Yan, Shuangshuang; Qiu, Li; Ma, Ke; Zhang, X; Zhao, Yawen; Zhang, J; Li, X; Hao, Xishan; Li, Z

doi:10.1038/onc.2013.494

Cited by 21 publications

(25 citation statements)

References 39 publications

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“…Thus the role of NKX3.1 in the DNA damage response may extend to affecting P53 as well. Other genes with known oncogenic potential were also placed downstream of NKX3.1 gene loss including chromosome 10 open ready frame 90, C10orf90 ( FATS ), that has been implicated as an activator of P53 expression (44, 45) and neuroblastoma break point family 1, NBPF1 , that has been disrupted in human cancer (46). …”

Section: Discussionmentioning

confidence: 99%

NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

2015

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TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor-mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2-ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement.

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Section: Discussionmentioning

confidence: 99%

NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

2015

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“…The ALMS motif is the only region that shares obvious sequence similarity with other human proteins. It was defined on the basis of similarity to mammalian orthologues of C10orf90/FATS (fragile site-associated tumour suppressor) [ 11 ], reportedly an E2-independent ubiquitin ligase which stabilises p53 in response to DNA damage [ 83 ] and may localise to the centrosome and actin cytoskeleton [ 21 ]. A more divergent ALMS motif was subsequently identified at the C-terminus of CEP295/KIAA1731 [ 21 ], a large protein implicated in centriole assembly and maintenance [ 21 , 84 – 87 ].…”

Section: The Alms1 Proteinmentioning

confidence: 99%

ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits

Hearn

2018

J Mol Med

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Alström syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis. Elucidating the function of the mutated gene, ALMS1, is critical for the development of specific treatments and may uncover pathways relevant to a range of other disorders including common forms of obesity and type 2 diabetes. Interest in ALMS1 is heightened by the recent discovery of its involvement in neonatal cardiomyocyte cell cycle arrest, a process with potential relevance to regenerative medicine. ALMS1 encodes a ~ 0.5 megadalton protein that localises to the base of centrioles. Some studies have suggested a role for this protein in maintaining centriole-nucleated sensory organelles termed primary cilia, and AS is now considered to belong to the growing class of human genetic disorders linked to ciliary dysfunction (ciliopathies). However, mechanistic details are lacking, and recent studies have implicated ALMS1 in several processes including endosomal trafficking, actin organisation, maintenance of centrosome cohesion and transcription. In line with a more complex picture, multiple isoforms of the protein likely exist and non-centrosomal sites of localisation have been reported. This review outlines the evidence for both ciliary and extra-ciliary functions of ALMS1.

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“…A Flag-FATS plasmid was constructed as previously described in detail 16 . A plasmid with an in-frame GFP-FATS fusion was constructed by inserting the full-length FATS cDNA into the vector pEGFP-C1 (Sigma, Buchs, Switzerland).…”

Section: Plasmids and Cloningmentioning

confidence: 99%

“…Having demonstrated that FATS regulates the expression of ODC, we subsequently performed immunoprecipitation assays to assess whether FATS directly binds to ODC, and the result was negative (data not shown). FATS is primarily localized in the nucleus 16 , whereas ODC is localized in the cytoplasm and membrane 32 . Therefore, we next investigated how FATS can indirectly regulate ODC.…”

Section: Fats Erβ and Odc Bind To Each Othermentioning

confidence: 99%

“…Fragile-site associated tumour suppressor (FATS) is a novel gene involved in cancer that is located at chromosome 10q26 and plays a key role in regulating tumour growth. The results of our previous study showed that FATS acts as a tumour suppressor involved in DNAdamage-induced tumourigenesis 15 , with FATS-mediated polyubiquitination of p53 promoting the activation of p53 in response to DNA damage 16 . Decreased FATS expression has been detected in breast cancer and was shown to be crucial for tumour growth, metastasis and therapy resistance.…”

Section: Introductionmentioning

confidence: 97%

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FATS regulates polyamine biosynthesis by promoting ODC degradation in an ERβ-dependent manner in non-small-cell lung cancer

Qiu

Wang

et al. 2020

Cell Death Dis

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Polyamine biosynthesis is an essential metabolic pathway for cell growth and differentiation in non-small-cell lung cancer (NSCLC). Fragile-site associated tumour suppressor (FATS) is a novel gene involved in cancer. The results of our previous study showed that FATS-mediated polyubiquitination of p53 promotes the activation of p53 in response to DNA damage; however, little is known about the role of FATS in metabolic reprogramming in NSCLC. In the present study, FATS was observed to be significantly downregulated in NSCLC tissues compared with paired adjacent normal tissues and was associated with the survival of NSCLC patients. We further showed that the presence of the tumour suppressor FATS in NSCLC cells led to apoptosis by inducing pro-death autophagy. In addition, FATS was shown to function as a suppressor of polyamine biosynthesis by inhibiting ornithine decarboxylase (ODC) at the protein and mRNA levels, which was partially dependent on oestrogen receptor (ER). Furthermore, FATS was observed to bind to ERβ and translocate to the cytosol, leading to ODC degradation. The findings of our study demonstrate that FATS plays important roles in polyamine metabolism in NSCLC and provides a new perspective for NSCLC progression.

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FATS is an E2-independent ubiquitin ligase that stabilizes p53 and promotes its activation in response to DNA damage

Cited by 21 publications

References 39 publications

NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits

FATS regulates polyamine biosynthesis by promoting ODC degradation in an ERβ-dependent manner in non-small-cell lung cancer

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