HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin–proteasome pathway

Wang, Xiaozhen; Lu, Guang; Li, Li; Yi, Juan; Ke, Yan; Wang, Yaqing; Zhu, Baili; Kuang, Jingyu; Lin, Ming Tseh; Sha, Zhang; Shao, Genze

doi:10.1016/j.bbrc.2014.01.075

Cited by 41 publications

(43 citation statements)

References 33 publications

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“…1C). Evidence suggests that both Huwe1 and Ubr5 participate in the negative regulation of BRCA1-mediated homologous recombination (65)(66)(67). Like Sec8, depletion of Huwe1 resulted in the accumulation of ATF2 (Fig.…”

Section: Resultsmentioning

confidence: 94%

Role of the Exocyst Complex Component Sec6/8 in Genomic Stability

Torres

Pandita

Kulak

et al. 2015

Molecular and Cellular Biology

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The exocyst is a heterooctomeric complex well appreciated for its role in the dynamic assembly of specialized membrane domains. Accumulating evidence indicates that this macromolecular machine also serves as a physical platform that coordinates regulatory cascades supporting biological systems such as host defense signaling, cell fate, and energy homeostasis. The isolation of multiple components of the DNA damage response (DDR) as exocyst-interacting proteins, together with the identification of Sec8 as a suppressor of the p53 response, suggested functional interactions between the exocyst and the DDR. We found that exocyst perturbation resulted in resistance to ionizing radiation (IR) and accelerated resolution of DNA damage. This occurred at the expense of genomic integrity, as enhanced recombination frequencies correlated with the accumulation of aberrant chromatid exchanges. Sec8 perturbation resulted in the accumulation of ATF2 and RNF20 and the promiscuous accumulation of DDR-associated chromatin marks and Rad51 repairosomes. Thus, the exocyst supports DNA repair fidelity by limiting the formation of repair chromatin in the absence of DNA damage. The faithful repair of DNA damage is integral to the maintenance of the genome and suppression of oncogenesis (1). This relationship has motivated intense efforts to elaborate the composition and mechanism of action of core DNA repair machinery as well as peripheral molecular systems that modulate this machinery to suppress genomic instability (2-5). With respect to the latter, emerging evidence implicates multiple regulatory layers that link activation of the DNA damage response (DDR), repair pathway choice, and resolution of the DDR to chromatin organization (6-9), RNA metabolism (10, 11), and autophagy (12)(13)(14). By extrapolation, the coordinated response of cellular processes to DNA damage is necessary for efficient DNA repair, and perturbations of these pathways can lead to genomic instability and development of neoplastic disease.The exocyst (also known as the Sec6/8 complex) is a conserved heterooctomeric protein complex, which includes Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo84, and Exo70. The holocomplex is well appreciated for its role in the dynamic trafficking of secretory vesicles to specialized membrane domains such as the basolateral membrane of polarized epithelial cells (15) and abscission planes in dividing cells (16) and to lamellipodia and growth cones of migrating cells and differentiating neurons (17, 18). Accumulating evidence indicates that exocyst subcomplexes, and their regulation by Ras and Rho family GTPases, also selectively participate in the assembly and activation of signal transduction events that mediate host defense, autophagy, cell growth, and oncogene signaling (19-23). An overarching implication is that the exocyst and its subcomplexes serve as physical platforms that coordinate organellar assembly with the activation of attendant regulatory cascades required for the execution of distinct cell biological programs.Here, we ...

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Section: Resultsmentioning

confidence: 94%

Role of the Exocyst Complex Component Sec6/8 in Genomic Stability

Torres

Pandita

Kulak

et al. 2015

Molecular and Cellular Biology

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“…B), the mechanism of which remains to be elucidated. It is noteworthy that DNA damage may promote the translocation of HUWE1 from the cytoplasm to the nucleus , suggesting another mechanism that regulates the interaction between Chk1 and HUWE1 as Chk1 predominantly localizes to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1

et al. 2019

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The HECT E3 ubiquitin ligase HUWE1 is required for a wide array of important functions in cell biology. Although HUWE1 is known to play a role in DNA damage signaling, the mechanism(s) that underlie this function remain elusive. HUWE1 regulates effectors of DNA replication and genotoxic stress tolerance. However, the loss of HUWE1 can also result in the accrual of significant endogenous DNA damage due to insufficient remediation of replication stress induced by an overabundance of key substrates. We discovered that HUWE1 depletion leads to a significant increase in levels of the single-strand break effector kinase Chk1, independent of the DNA damage response, activation of apical DNA damage repair (DDR) signaling kinases (ATM and ATR), and the tumor suppressor p53. We also identified multiple lysine residues on Chk1 that are polyubiquitinated by HUWE1 in vitro, many of which are within the kinase domain. HUWE1 knockdown also markedly prolonged the protein half-life of Chk1 in steadystate conditions and resulted in greater stabilization of Chk1 protein than depletion of Cul4A, an E3 ubiquitin ligase previously described to control Chk1 abundance. Moreover, prolonged replication stress induced by hydroxyurea or camptothecin resulted in a reduction of Chk1 protein levels, which was rescued by HUWE1 knockdown. Our study indicates that HUWE1 plays a significant role in the regulation of the DDR signaling pathway by directly modulating the abundance of Chk1 protein.

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“…Our finding that, in addition to increased levels of DNA damage, Huwe1 ‐deficient tumours display additional sensitivity to DNA‐damaging agents is in agreement with previous reports (Farmer et al , ; Hay et al , ). A number of previous studies have identified HUWE1 as an important mediator of DNA repair via modulation of proteins such as MUTY, BRCA1, POLB and TP53 (Chen et al , ; Parsons et al , ; Dorn et al , ; Wang et al , ). Interestingly, alongside mediating DNA damage response, a recent paper has identified a mechanism via which Huwe1 loss can drive DNA damage accumulation.…”

Section: Discussionmentioning

confidence: 99%

HUWE 1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation

et al. 2016

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Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc. The increased levels of DNA damage sensitised Huwe1‐deficient tumours to DNA‐damaging agents and to deletion of the anti‐apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a potential vulnerability of HUWE1‐mutated tumours to DNA‐damaging agents and inhibitors of anti‐apoptotic proteins.

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HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin–proteasome pathway

Cited by 41 publications

References 33 publications

Role of the Exocyst Complex Component Sec6/8 in Genomic Stability

Role of the Exocyst Complex Component Sec6/8 in Genomic Stability

Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1

HUWE 1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation

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