The deubiquitinase USP36 Regulates DNA replication stress and confers therapeutic resistance through PrimPol stabilization

Yan, Yuanliang; Xu, Zhijie; Huang, Jinzhou; Guo, Guijie; Gao, Ming; Kim, Wootae; Zeng, Xiangyu; Kloeber, Jake A.; Zhu, Qian; Zhao, Fei; Luo, Kuntian; Lou, Zhenkun

doi:10.1093/nar/gkaa1090

Cited by 37 publications

(31 citation statements)

References 51 publications

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“…The increase in mRNA was found to be regulated by ATR. Another recent study reported that the USP36 protease also possibly plays a role in regulating PrimPol protein levels ( 152 ), and the ATPase WRNIP1 has been suggested to target PrimPol protein for degradation ( 153 ). This suggests that multiple mechanisms exist that regulate PrimPol deployment in human cells.…”

Section: Introduction: the Eukaryotic Dna Replication Machinerymentioning

confidence: 99%

Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication

Bainbridge

Teague

Doherty

2021

Nucleic Acids Research

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To bypass a diverse range of fork stalling impediments encountered during genome replication, cells possess a variety of DNA damage tolerance (DDT) mechanisms including translesion synthesis, template switching, and fork reversal. These pathways function to bypass obstacles and allow efficient DNA synthesis to be maintained. In addition, lagging strand obstacles can also be circumvented by downstream priming during Okazaki fragment generation, leaving gaps to be filled post-replication. Whether repriming occurs on the leading strand has been intensely debated over the past half-century. Early studies indicated that both DNA strands were synthesised discontinuously. Although later studies suggested that leading strand synthesis was continuous, leading to the preferred semi-discontinuous replication model. However, more recently it has been established that replicative primases can perform leading strand repriming in prokaryotes. An analogous fork restart mechanism has also been identified in most eukaryotes, which possess a specialist primase called PrimPol that conducts repriming downstream of stalling lesions and structures. PrimPol also plays a more general role in maintaining efficient fork progression. Here, we review and discuss the historical evidence and recent discoveries that substantiate repriming as an intrinsic replication restart pathway for maintaining efficient genome duplication across all domains of life.

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Section: Introduction: the Eukaryotic Dna Replication Machinerymentioning

confidence: 99%

Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication

Bainbridge

Teague

Doherty

2021

Nucleic Acids Research

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“…Staining intensity was scored using a four-point scale as follows: 3, strong (tan); 2, medium (brown-yellow); 1, weak (light yellow); and 0, none. The proportion of positive cells was scored as 0, 0%; 1, ≤10%; 2, 11–50%; 3, 51–75%; and 4, >75% ( 20 ). The staining index (SI) was determined as the sum of the staining intensity score and the number of positive cells.…”

Section: Methodsmentioning

confidence: 99%

Plasma‑derived exosomal pyruvate kinase isoenzyme type M2 accelerates the proliferation and motility of oesophageal squamous cell carcinoma cells

Yang

Liu

et al. 2021

Oncol Rep

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Exosomal pyruvate kinase isoenzyme type M2 (PKM2) has been found to play a key role in the progression of human hepatocarcinoma. However, exosomal PKM2 (especially plasma-derived exosomal PKM2), in patients with oesophageal squamous cell carcinoma (ESCC) has not been well defined. In the present study, plasma-derived exosomes were isolated from healthy controls and patients with ESCC, and identified by transmission electronic microscopy, western blotting, nano-flow cytometry, nanoparticle tracking and phagocytosis analysis; exosomal PKM2 was detected by western blotting and ELISA. In addition, changes in cellular proliferation and motility in recipient cells (Eca109) were assessed using Cell Counting Kit-8, colony formation, wound-healing and Transwell assays. The PKM2 content was higher in exosomes from patients with ESCC than in those from healthy donors. Furthermore, exosomes from patients with ESCC enhanced the proliferation and motility of ESCC cells in vitro. Notably, PKM2 was found to be transferred by exosomes, and was able to act by activating STAT3. To verify the association between PKM2 and STAT3, immunohistochemistry was employed to analyse the protein levels of PKM2 and pSTAT3 Tyr705 . These data revealed that PKM2 and pSTAT3 Tyr705 were upregulated and associated with overall survival in patients with ESCC. Therefore, the present study highlights that exosomes from patients with ESCC enhance the migration and invasiveness of ESCC cells by transferring PKM2.

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“…Ubiquitinase and deubiquitinase, therefore, make them effective therapeutic targets against drug resistance by epigenetic regulation of a variety of cancer-related pathways and their ability to regulate atypical drug targets such as transcription factors and skeleton proteins (53). It has been reported that deubiquitinase is abnormally activated in a variety of cancers, resulting in increased protein expression related to drug efflux and changes in drug target molecules (54), activating a variety of oncogenic pathways and forming drug resistance (55)(56)(57), so deubiquitinase has the potential to be developed as drug targets. It is therefore essential to study the ubiquitylome of cancers to provide new ideas for new drug target development.…”

Section: Discussionmentioning

confidence: 99%

Identification of ubiquitinated substrate proteins and their gene expression patterns in lung adenocarcinoma

Xu¹,

Lu²,

Zhao³

et al. 2021

Ann Transl Med

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Background: Lung cancer is a malignant disease with the highest cancer-related mortality rate. In lung adenocarcinoma (LUAD), protein ubiquitination can regulate multiple biological processes. A LUAD ubiquitylome analysis has not yet been reported. Methods:We used for the first time ion mobility into liquid chromatography-mass spectrometry to perform accurate and reliable ubiquitylome and proteomic analysis of clinical LUAD and normal tissues and combined it with transcriptome data obtained from public databases. Ubiquitinated protein substrates and their gene expression pattern landscapes in LUAD were identified using bioinformatics methods.Results: Our data revealed a ubiquitination landscape in LUAD and identified characteristic protein ubiquitination motifs. We found that the ubiquitinated peptide motifs in LUAD were completely different from those of previously published lung squamous cell carcinoma (LUSC). Moreover, we identified two gene expression patterns of ubiquitinated proteins and revealed that survival differences between these patterns may be correlated with the tumor immune infiltrating microenvironment. Finally, we constructed a prognostic predictive model to quantify the relationship between expression patterns and survival. We found a relationship between the patient-applied model score and multiple drug sensitivity. Therefore, our model can serve as a guide for LUAD clinical treatment.Conclusions: Our work addresses the lack of ubiquitylome studies in LUAD and provides new perspectives for subsequent research and clinical treatment.

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The deubiquitinase USP36 Regulates DNA replication stress and confers therapeutic resistance through PrimPol stabilization

Cited by 37 publications

References 51 publications

Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication

Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication

Plasma‑derived exosomal pyruvate kinase isoenzyme type M2 accelerates the proliferation and motility of oesophageal squamous cell carcinoma cells

Identification of ubiquitinated substrate proteins and their gene expression patterns in lung adenocarcinoma

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