Trip12 is an E3 ubiquitin ligase for <scp>USP</scp>7/<scp>HAUSP</scp> involved in the <scp>DNA</scp> damage response

Liu, Xiaoliang; Yang, Xin; Li, Yongxin; Song, Zhao; Li, Chaocui; Ma, Ping; Mao, Bingyu

doi:10.1002/1873-3468.12471

Cited by 47 publications

(30 citation statements)

References 41 publications

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“…Further proteomic studies of the RNF169-DYRK1A complex in the cells before and after DNA damage will help to identify such factor. Of note, our analysis of DYRK1A interactome reported here detected the interaction with USP7, a ubiquitin-specific protease that has been recently shown to bind directly to RNF169 and increase the stability of 53BP1, RNF169 and RNF168 [40,[65][66][67]. Although disruption of the DYRK1A phosphorylation sites in RNF169 did not influence its interaction with USP7, the role of USP7 in the DYRK1A-RNF 169 mediated regulation of 53BP1 should be further investigated.…”

Section: Discussionmentioning

confidence: 68%

DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169

et al. 2019

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Human Dual-specificity tyrosine (Y) Regulated Kinase 1A (DYRK1A) is encoded by a dosage dependent gene whereby either trisomy or haploinsufficiency result in developmental abnormalities. However, the function and regulation of this important protein kinase are not fully understood. Here, we report proteomic analysis of DYRK1A in human cells that revealed a novel role of DYRK1A in DNA doublestrand breaks (DSBs) repair, mediated in part by its interaction with the ubiquitin-binding protein RNF169 that accumulates at the DSB sites and promotes homologous recombination repair (HRR) by displacing 53BP1, a key mediator of non-homologous end joining (NHEJ). We found that overexpression of active, but not the kinase inactive DYRK1A in U-2 OS cells inhibits accumulation of 53BP1 at the DSB sites in the RNF169-dependent manner. DYRK1A phosphorylates RNF169 at two sites that influence its ability to displace 53BP1 from the DSBs. Although DYRK1A is not required for the recruitment of RNF169 to the DSB sites and 53BP1 displacement, inhibition of DYRK1A or mutation of the DYRK1A phosphorylation sites in RNF169 decreases its ability to block accumulation of 53BP1 at the DSB sites. Interestingly, CRISPR-Cas9 knockout of DYRK1A in human and mouse cells also diminished the 53BP1 DSB recruitment in a manner that did not require RNF169, suggesting that dosage of DYRK1A can influence the DNA repair processes through both RNF169-dependent and independent mechanisms. Human U-2 OS cells devoid of DYRK1A display an increased HRR efficiency and resistance to DNA damage, therefore our findings implicate DYRK1A in the DNA repair processes.

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Section: Discussionmentioning

confidence: 68%

DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169

et al. 2019

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“…68 On another hand, overexpression of TRIP12 (R SILAC = 1.62) produces inhibition of USP7, which is an ubiquitin specific processing protease whose depletion induce cell cycle arrest at the S phase. 69 The inhibition of a big part of the proteins found altered in the study also has effects on cell proliferation. Different studies carried out in hepatocarcinoma cells such as Huh-7 or HepG2 (cells employed in our work) have shown that an inhibition of SHMT2 (R SILAC = 2.26) or RFC3 (R SILAC = 1.91), is translated into an inhibition of cell proliferation and tumorigenicity 70 by stabilization of p21, p53 and p57, and the inhibition of the cyclin A.…”

Section: Quantitative Proteomicsmentioning

confidence: 90%

Cancer cell targeting and therapeutic delivery of silver nanoparticles by mesoporous silica nanocarriers: insights into the action mechanisms using quantitative proteomics

et al. 2019

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“…Unsurprisingly, overexpression of USP7 and TRIP12 has been found to be associated with poor prognosis in cancers with aberrant expression of p14 ARF , such as hepatocellular carcinoma (HCC) [131]. Interestingly, USP7 itself is also targeted by TRIP12 for proteasomal degradation, indicating that they are mutual substrates for each other [132]. Thus, USP7 increases the stability of TRIP12, whereas the TRIP12 does the opposite for USP7.…”

Section: Substrate Recruitment and Catalytic Activity Regulationmentioning

confidence: 99%

Regulating the human HECT E3 ligases

Sluimer

Distel

2018

Cell. Mol. Life Sci.

122

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Ubiquitination, the covalent attachment of ubiquitin to proteins, by E3 ligases of the HECT (homologous to E6AP C terminus) family is critical in controlling diverse physiological pathways. Stringent control of HECT E3 ligase activity and substrate specificity is essential for cellular health, whereas deregulation of HECT E3s plays a prominent role in disease. The cell employs a wide variety of regulatory mechanisms to control HECT E3 activity and substrate specificity. Here, we summarize the current understanding of these regulatory mechanisms that control HECT E3 function. Substrate specificity is generally determined by interactions of adaptor proteins with domains in the N-terminal extensions of HECT E3 ligases. These N-terminal domains have also been found to interact with the HECT domain, resulting in the formation of inhibitory conformations. In addition, catalytic activity of the HECT domain is commonly regulated at the level of E2 recruitment and through HECT E3 oligomerization. The previously mentioned regulatory mechanisms can be controlled through protein–protein interactions, post-translational modifications, the binding of calcium ions, and more. Functional activity is determined not only by substrate recruitment and catalytic activity, but also by the type of ubiquitin polymers catalyzed to the substrate. While this is often determined by the specific HECT member, recent studies demonstrate that HECT E3s can be modulated to alter the type of ubiquitin polymers they catalyze. Insight into these diverse regulatory mechanisms that control HECT E3 activity may open up new avenues for therapeutic strategies aimed at inhibition or enhancement of HECT E3 function in disease-related pathways.

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Trip12 is an E3 ubiquitin ligase for USP7/HAUSP involved in the DNA damage response

Cited by 47 publications

References 41 publications

DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169

DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169

Cancer cell targeting and therapeutic delivery of silver nanoparticles by mesoporous silica nanocarriers: insights into the action mechanisms using quantitative proteomics

Regulating the human HECT E3 ligases

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