BRCC3 acts as a prognostic marker in nasopharyngeal carcinoma patients treated with radiotherapy and mediates radiation resistance in vitro

Tu, Ziwei; Xu, Bingqing; Qu, Chen; Tao, Yijing; Chen, Chen; Hua, Wenfeng; Feng, Guokai; Chang, Hui; Liu, Zhigang; Li, Guo; Jiang, Changbin; Yi, Wei; Zeng, Mu‐Sheng; Xia, Yunfei

doi:10.1186/s13014-015-0427-3

Cited by 27 publications

(30 citation statements)

References 39 publications

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“…Depletion of BRCC36 compromised the G 2 /M cell cycle checkpoint, impaired BRCA1 recruitment onto DSBs, resulted in hyperactive homologous recombination (HR)-based gene conversion events and hypersensitized the cell to genotoxic stress (7)(8)(9)(10)(11)(12). Consistent with the idea that dysregulated DNA repair promotes tumorigenesis, aberrant expression of BRCC36 has been associated with breast carcinomas (19) and nasopharyngeal carcinomas (20) and represents a promising prognostic marker and a potential target in the therapies for these cancer types. Although BRCC36 has emerged as an essential enzymatic activity in the mammalian DDR, the metabolism of K63-Ub chains and its contribution to DDRs remain obscure.…”

mentioning

confidence: 52%

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

Ng¹,

Wei

Lan

et al. 2016

Journal of Biological Chemistry

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Multisubunit protein assemblies offer integrated functionalities for efficient cell signal transduction control. One example of such protein assemblies, the BRCA1-A macromolecular complex, couples ubiquitin recognition and metabolism and promotes cellular responses to DNA damage. Specifically, the BRCA1-A complex not only recognizes Lys 63 -linked ubiquitin (K63-Ub) adducts at the damaged chromatin but is endowed with K63-Ub deubiquitylase (DUB) activity. To explore how the BRCA1-A DUB activity contributes to its function at DNA double strand breaks (DSBs), we used RNAi and genome editing approaches to target BRCC36, the protein subunit that confers the BRCA1-A complex its DUB activity. Intriguingly, we found that the K63-Ub DUB activity, although dispensable for maintaining the integrity of the macromolecular protein assembly, is important in enforcing the accumulation of the BRCA1-A complex onto DSBs. Inactivating BRCC36 DUB attenuated BRCA1-A functions at DSBs and led to unrestrained DSB end resection and hyperactive DNA repair. Together, our findings uncover a pivotal role of BRCC36 DUB in limiting DSB processing and repair and illustrate how cells may physically couple ubiquitin recognition and metabolizing activities for fine tuning of DNA repair processes. Active hydrolysis of ubiquitin polymers by deubiquitylases (DUBs)2 has emerged as important biochemical processes that underlie diverse signal transduction pathways, including cell responses to DNA damage (1). To date, around 94 human DUBs have been identified and are classified into five families: ubiquitin C-terminal hydrolases, ubiquitin-specific proteases, ovarian tumor proteases, Josephins, and JAB1/MPN/MOV4 metalloproteases. Notably, the JAB1/MPN/MOV4 metalloprotease family members are zinc-dependent metalloproteases, and the other families are cysteine proteases (1).BRCC36, originally reported as the BRCA1/BRCA2-containing complex subunit 36 (2), is endowed with DUB activity for lysine 63-linked ubiquitin polymers (K63-Ub). BRCC36 DUB relies on its zinc-dependent JAB1/MPN/MOV4 metalloprotease domain (3) and its interaction with Abraxas/KIAA0157 (3-5). Although BRCC36 forms distinct nuclear and cytoplasmic complexes (5, 6) and plays pleiotropic roles during cell proliferation, the K63-Ub DUB is arguably best known for its strong links with the breast and ovarian susceptible gene product BRCA1 in DNA damage responses (DDRs). Indeed, BRCC36 resides within the BRCA1-A macromolecular protein complex, which comprises the ubiquitin-binding protein RAP80, BRCC45/BRE, Abraxas/CCDC98, Merit40/NBA1, and BRCA1. The BRCA1-A complex is targeted to chromatin domains surrounding DNA double strand breaks (DSBs) by the ubiquitin-binding protein RAP80, which preferentially binds to K63-Ub adducts generated by the ubiquitin-conjugating enzyme UBC13 (3, 7-12). Abraxas plays a major scaffolding role to support the integrity of the BRCA1-A assembly and directly anchors the tumor suppressor BRCA1 via a phosphorylation-dependent interaction (13-15). Indeed, BRCA1, via it...

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mentioning

confidence: 52%

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

Ng¹,

Wei

Lan

et al. 2016

Journal of Biological Chemistry

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“…Although local radiation, surgery, and other combining treatments, and advantage to concurrent chemoradiation in the treatment of advanced disease provide good control of the most NPC, the prognosis of certain patients with NPC still remains poor due to the fact of advanced stage at the time of diagnosis, regional relapse, and distant metastasis. In addition, the high radiotherapy resistance is a severe obstacle for the treatment of NPC [16, 17]. Moreover, adverse effects, including upper gastrointestinal impairment and bone marrow suppression, depressed the toleration, and limited outcome of concurrent chemo-radiotherapies may affect the quality of life and survival in NPC patients.…”

Section: Introductionmentioning

confidence: 99%

Functions and Roles of Long-Non-Coding RNAs in Human Nasopharyngeal Carcinoma

Hann²

2018

Cell Physiol Biochem

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Nasopharyngeal carcinoma (NPC) is one of the most common cancers originating in the nasopharynx and occurring at high frequency in South-eastern Asia and North Africa. Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNA molecules and key regulators of developmental, physiological, and pathological processes in humans. Emerging studies have shown that lncRNAs play critical roles in tumorgenicity and cancer prognosis. With the development of deep sequencing analyses, an extensive amount of functional lncRNAs have been discovered in nasopharyngeal carcinoma tissues and cell lines. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of NPC are not fully understood. In this review, we briefly illustrate the concept, identification, functional characterization, and summarize recent advancements of biological functions of lncRNAs with heterogeneous mechanistic characterization and their involvement in NPC. Then, we describe individual lncRNAs that have been associated with tumorgenesis, growth, invasion, cancer stem cell differentiation, metastasis, drug resistance and discuss the strategies of their therapeutic manipulation in NPC. We also review the emerging insights into the role of lncRNAs and their potential as biomarkers and therapeutic targets for novel treatment paradigms. Finally, we highlight the up-to-date of clinical information involving lncRNAs and future directions in the linking lncRNAs to potential gene therapies, and how modifications of lncRNAs can be exploited for prevention and treatment of NPC.

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“…The surviving fractions (SF) were then calculated by dividing the PE by the PE of the non‐irradiated control. The radiation dose‐clonogenic survival curves were fit to a linear‐quadratic model as previously described . The curves were compared using the extra sum‐of‐squares F‐test in GraphPad Prism 6.0 (GraphPad Software, La Jolla, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…After 24 hrs, the plates with cells were irradiated at a dose of 2 Gy. The immunofluorescence analysis was performed as described previously . For γH2AX, the cells were analysed 0, 0.5, 12 and 24 hrs after irradiation.…”

Section: Methodsmentioning

confidence: 99%

“…It can bind to ssDNA strands with high affinity and is required for many DNA metabolism processes, including the homologous recombination (HR) repair of DNA double‐strand breaks (DSBs) . Moreover, the DNA repair capacity correlates with radiosensitivity . Accordingly, high RPA1 and RPA2 expression levels reportedly increased radioresistance in oesophageal cancer and predicted a poor prognosis in oesophageal cancer , colon cancer , astrocytic tumours and bladder urothelial cancer .…”

Section: Introductionmentioning

confidence: 99%

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RPA3 is a potential marker of prognosis and radioresistance for nasopharyngeal carcinoma

Zhao

Feng

et al. 2017

J Cellular Molecular Medi

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Radioresistance‐induced residual and recurrent tumours are the main cause of treatment failure in nasopharyngeal carcinoma (NPC). Thus, the mechanisms of NPC radioresistance and predictive markers of NPC prognosis and radioresistance need to be investigated and identified. In this study, we identified RPA3 as a candidate radioresistance marker using RNA‐seq of NPC samples. In vitro studies further confirmed that RPA3 affected the radiosensitivity of NPC cells. Specifically, the overexpression of RPA3 enhanced radioresistance and the capacity for DNA repair of NPC cells, whereas inhibiting RPA3 expression sensitized NPC cells to irradiation and decreased the DNA repair capacity. Furthermore, the overexpression of RPA3 enhanced RAD51 foci formation in NPC cells after irradiation. Immunohistochemical assays in 104 NPC specimens and 21 normal epithelium specimens indicated that RPA3 was significantly up‐regulated in NPC tissues, and a log‐rank test suggested that in patients with NPC, high RPA3 expression was associated with shorter overall survival (OS) and a higher recurrence rate compared with low expression (5‐year OS rates: 67.2% versus 86.2%; 5‐year recurrence rates: 14.8% versus 2.3%). Moreover, TCGA data also indicated that high RPA3 expression correlated with poor OS and a high recurrence rate in patients with head and neck squamous cell carcinoma (HNSC) after radiotherapy. Taken together, the results of our study demonstrated that RPA3 regulated the radiosensitivity and DNA repair capacity of NPC cells. Thus, RPA3 may serve as a new predictive biomarker for NPC prognosis and radioresistance to help guide the diagnosis and individualized treatment of patients with NPC.

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BRCC3 acts as a prognostic marker in nasopharyngeal carcinoma patients treated with radiotherapy and mediates radiation resistance in vitro

Cited by 27 publications

References 39 publications

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

Functions and Roles of Long-Non-Coding RNAs in Human Nasopharyngeal Carcinoma

RPA3 is a potential marker of prognosis and radioresistance for nasopharyngeal carcinoma

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