更新于：2024-05-01

WDR48

WD repeat domain 48

更新于：2024-05-01

基本信息

别名

Bun62、KIAA1449、P80

+ [7]

简介

(Microbial infection) In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP (PubMed:12196293). In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1 (PubMed:18032488). Regulator of deubiquitinating complexes, which acts as a strong activator of USP1, USP12 and USP46 (PubMed:18082604, PubMed:19075014, PubMed:31253762, PubMed:26388029). Enhances the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself (PubMed:18082604, PubMed:31253762). Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate (PubMed:19075014, PubMed:27373336). Also activates deubiquitinating activity of complexes containing USP12 (PubMed:19075014, PubMed:27650958, PubMed:27373336). In complex with USP12, acts as a potential tumor suppressor by positively regulating PHLPP1 stability (PubMed:24145035). Docks at the distal end of the USP12 fingers domain and induces a cascade of structural changes leading to the activation of the enzyme (PubMed:27650958, PubMed:27373336). Together with RAD51AP1, promotes DNA repair by stimulating RAD51-mediated homologous recombination (PubMed:27463890, PubMed:27239033, PubMed:32350107). Binds single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) (PubMed:27239033, PubMed:31253762, PubMed:32350107). DNA-binding is required both for USP1-mediated deubiquitination of FANCD2 and stimulation of RAD51-mediated homologous recombination: both WDR48/UAF1 and RAD51AP1 have coordinated role in DNA-binding during these processes (PubMed:31253762, PubMed:32350107). Together with ATAD5 and by regulating USP1 activity, has a role in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA (PubMed:20147293). Together with ATAD5, has a role in recruiting RAD51 to stalled forks during replication stress (PubMed:31844045).

关联

100 项与 WDR48 相关的临床结果

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100 项与 WDR48 相关的转化医学

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0 项与 WDR48 相关的专利（医药）

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101

项与 WDR48 相关的文献（医药）

2024-01-01·RNA biology

CCAR-1 works together with the U2AF large subunit UAF-1 to regulate alternative splicing.

Article

作者: Doreen I Lugano ; Lindsey N Barrett ; Dale Chaput ; Margaret A Park ; Sandy D Westerheide

The Cell Division Cycle and Apoptosis Regulator (CCAR) protein family members have recently emerged as regulators of alternative splicing and transcription, as well as having other key physiological functions. For example, mammalian CCAR2/DBC1 forms a complex with the zinc factor protein ZNF326 to integrate alternative splicing with RNA polymerase II transcriptional elongation in AT-rich regions of the DNA. Additionally, Caenorhabditis elegans CCAR-1, a homolog to mammalian CCAR2, facilitates the alternative splicing of the perlecan unc-52 gene. However, much about the CCAR family's role in alternative splicing is unknown. Here, we have examined the role of CCAR-1 in genome-wide alternative splicing in Caenorhabditis elegans and have identified new alternative splicing targets of CCAR-1 using RNA sequencing. Also, we found that CCAR-1 interacts with the spliceosome factors UAF-1 and UAF-2 using mass spectrometry, and that knockdown of ccar-1 affects alternative splicing patterns, motility, and proteostasis of UAF-1 mutant worms. Collectively, we demonstrate the role of CCAR-1 in regulating global alternative splicing in C. elegans and in conjunction with UAF-1.

2023-12-06·Journal of immunology (Baltimore, Md. : 1950)

The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.

Article

作者: Zhongxia Yu ; Li Tong ; Chenkai Ma ; Hui Song ; Jie Wang ; Li Chai ; Caiwei Wang ; Mengge Wang ; Chunying Wang ; Rongzhen Yan ; Yue Fu ; Mutian Jia ; Wei Zhao ; Chunyuan Zhao

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.

2023-12-01·Regenerative therapy

Transcriptomic analysis of hepatocytes reveals the association between ubiquitin-specific peptidase 1 and yes-associated protein 1 during liver regeneration.

Article

作者: Yalei Zhao ; Fen Zhang ; Xiaoli Zhang ; Zuhong Li ; Qian Li ; Tianzhi Ni ; Ruojing Wang ; Liangru Liu ; Yingli He ; Yingren Zhao

Objectives:

The liver has an excellent ability to regenerate, and disrupted liver regeneration after various injuries leads to an unfavorable prognosis for patients. In this study, we sought to identify novel therapeutic hallmarks that are associated with yes-associated protein 1 (YAP1)-mediated hepatocyte proliferation during the process of liver regeneration.

Methods:

Partial hepatectomy was conducted to induce liver regeneration in rats. Primary hepatocytes were isolated and cultured. Hepatocyte proliferation was assessed using immunohistochemistry staining, and expression of YAP1 was detected. RNA sequencing and bioinformatics analysis were used to search for potential regulators of YAP1. The association between ubiquitin-specific peptidase 1 (USP1) and YAP1 was validated using in vivo and in vitro experiments.

Results:

YAP1 was significantly elevated in regenerative hepatocytes, especially in the nucleus. Knockdown of YAP1 using small interfering RNA or pharmacological inhibition using verteporfin significantly attenuated the proliferation of hepatocytes. The bioinformatics analysis results revealed that USP1 was associated with YAP1-mediated hepatocyte proliferation during liver regeneration. ML-323, a specific inhibitor of USP1-USP1 associated factor 1 (UAF1), significantly decreased the expression of YAP1, Cyclin D1, and proliferating cell nuclear antigen, while these decreased expressions could be rescued by YAP1 overexpression. Furthermore, ML-323 treatment significantly inhibited liver regeneration following partial hepatectomy.

Conclusions:

In conclusion, we identified USP1 as a novel biomarker that is associated with YAP1-mediated hepatocyte proliferation in liver regeneration. Pharmacological inhibition of USP1 by ML-323 substantially impairs hepatocyte proliferation during liver regeneration.

项与 WDR48 相关的新闻（医药）

2024-03-11

·药渡Daily

2024AACR的中国之声—合成致死靶点

USP1靶点海思科：HSK39775HSK39775是一种有效的、高选择性的泛素羧基末端水解酶1（USP1）抑制剂，可以在酶水平上具有抑制USP1/UAF1复合物的活性。三阴性BRCA突变乳腺癌异种移植模型显示HSK39775单药可剂量依赖性的抑制肿瘤生长，30mg/kg QD肿瘤生长抑制（TGI）为63.2%。同时与PARP抑制剂联用显着增强了HSK39775在异种移植模型中的治疗效果，即使在低剂量下也能实现肿瘤消退和持久的抑瘤作用[TGI：89%（HSK39775，5mg/kg+Olaparib，50mg/kg)] 。HSK39775单药可在HRD和BRCA野生型肺癌异种移植模型中抑制肿瘤生长，每日一次30mg/kg剂量的TGI为94%，这表明USP1抑制剂在典型的BRCA突变或HRD肿瘤之外也具有治疗效果。亚盛：ASN-3186ASN-3186是一种新型、有效、选择性的USP1抑制剂，其酶活分析IC50值为个位数纳摩尔，并且对其他家族成员的选择性>1000倍。ASN-3186在BRCA1m三阴性乳腺癌（TNBC）细胞系MDA-MB-436中抗增殖活性IC50<30nM。MDA-MB-436 CDX小鼠模型证实了ASN-3186体内的剂量依赖性单药抑制活性，其效力高于KSQ4279，这可能是由于ASN-3186具有更高的口服生物利用度。ASN-3186和PARPi抑制剂Olaparib联用，高剂量联用时几乎完全肿瘤消退。ASN-3186可显着提高了Olaparib在CAOV3（卵巢，HRD高）和MX-1（TNBC，BCRA1/2 mut）模型中的最小抗肿瘤活性，这些模型对 PAPRi具有耐药性；ASN-3186与DNA损伤药物吉西他滨联用，也观察到了合成致死活性。此外，ASN-3186显示出理想的ADME和PK特性，在不同物种中具有较高的口服生物利用度（>75%）。来凯医药：LAE120LAE120是一种新型变构高效USP1抑制剂，在生化测定中，LAE120强烈抑制USP1酶活性，IC50为5.6nM。LAE120有效抑制BRCA突变的MDA-MB-436乳腺癌细胞的增殖（IC50：19nM），并在NCI-H1792（IC50：69nM）和K562（IC50：38nM）细胞系中表现出抗增殖活性。在具有BRCA突变的MDA-MB-436细胞的异种移植模型中，LAE120单药肿瘤抑制活性良好（TGI：88%，10mg/kg BID），并观察到剂量依赖性反应（TGI：106%，25mg/kg BID）, 在Bcr-Abl表达的K562异种移植模型中观察到LAE120单药10mg/kg BID抑瘤作用显著TGI达到86%。Polθ靶点丹擎医药：DAT-1000ADAT-1000As一种新型小分子Polθ抑制剂，在MMEJ功能测定中的功效验证了其靶向细胞活性。与亲代细胞相比，HR缺陷型BRCA2-KO DLD-1细胞的细胞活力评估显示，其合成致死率窗口超过500倍；DAT-1000A在小鼠中的高剂量治疗未引起显著异常，表现出良好的耐受性。再鼎医药：ZL-2311ZM-2311可显著抑制Polθ活性IC50为24nM。在MDA-MB-436 SHLD2-/-异种移植模型中ZM-2311显示出强大抑瘤作用。ZM-2311与PARP抑制剂联用，在体外和体内对 BRCA2-/- DLD-1和内源性HR缺陷肿瘤细胞具有协同抗增殖活性。此外，ZM-2311与其他DDR药物（例如ATR抑制剂）联用可对HR缺陷细胞诱导致命的DNA损伤；ZM-2311还可与放化疗联用，ZM-2311使肿瘤细胞在体内外的HR缺陷和有效细胞中对放疗更敏感。圣域生物：SYX1097SYX1097具有高选择性可显着抑制 BRCA-/-同基因细胞的增殖IC50<20nM，对亲本细胞IC50>10000nM，SYX1097还将肿瘤细胞对Olaparib的敏感性增强了5至15倍。SYX1097在50mg/kg 单药治疗时体内有效，Olaparib联用时给药5mg/kg肿瘤消退>50%。在一项为期20天的重复给药研究中，SYX1097 200mg/kg BID被小鼠完全耐受。SYX1097在Safety-Screen 44TM Panel安全性评估中，在小鼠、大鼠和狗中具有良好的耐受性。它在不同物种中具有显着的药代动力学特性，在临床前毒性研究中未观察到血液学毒性。WRN靶点先声药业：ZM-3329ZM-3329是一种新型高效WRN抑制剂，可有效抑WRN酶活性IC50＜30nM，对HCT-116细胞增殖抑制具有同等效力。ZM-3329可特异性抑制MSI-H肿瘤细胞生长，但对MSS（微卫星稳定）肿瘤细胞系没有显着影响，表明对MSS具有高选择性。细胞内作用机制研究表明，ZM-3329在MSI-H细胞中抑制WRN会导致DNA损伤特征的累积，具体表现为γH2AX和P21表达增加，并将细胞周期阻滞至G2/M。在小鼠模型中对所有测试剂量均耐受良好，未观察到异常。勤浩医药：GH1581GH158s一种有效且选择性的WRN抑制剂。GH1581在体外ADP-Glo测定及MSI癌细胞系的细胞增殖测定中均显示出<10nM 的特异性效力。在体内研究中，GH1581在不同物种中表现出良好的药代动力学特性。在SW48异种移植模型中，10mg/kg QD剂量时，展现出TGI 100%抑制肿瘤生长，且对体重没有严重影响。英矽智能：ISM9342AISM9342A是一种新型有效的WRN抑制剂，在ATP酶和解旋酶测定中均显示出个位数的纳摩尔IC50值。ISM9342A抑制MSI-H癌细胞的增殖并增加双链断裂标记。此外，ISM9342A在MSI-H异种移植模型中表现出良好的体内抗肿瘤功效以及肿瘤消退。ISM9342A表现出良好的类药特性，具有良好的体外ADMET特性和体内暴露量，包括在多个临床前物种中的低清除率和最佳口服生物利用度。浦合医药：PH027-1PH027-1是一种高选择性、强效的WRN解旋酶活性抑制剂，生化检测显示，PH027-1有效抑制WRN解旋酶活性（IC50，0.8nM），即使在最高测试浓度10μM 下，对其他RecQ家族成员也没有影响（IC50，BLM均≥10μM， RecQ4和RecQ5)。同时，PH027-1在所有测试浓度下均不影响WRN的核酸外切酶活性。在基于细胞的测定中，PH027-1在数十nM 时可有效抑制MSI-H癌细胞SW48和HCT116的细胞活力，在10μM时对MSS细胞（HT29癌细胞和CD34+造血干细胞）也没有影响。测试进一步扩展到18种癌细胞系，涵盖子宫癌、胃癌、卵巢癌和结直肠癌。12个MSI-H细胞系中的9个对WRN抑制非常敏感，所有6种MSS细胞系对治疗完全耐药。体内PK研究显示PH027-1具有优异的PK特性，在小鼠、大鼠和狗中的绝对生物利用度为58%~102%。在两个CDX模型（SW48和HCT116）中，口服PH027-1剂量依赖性地抑制肿瘤生长，并且在20mg/kg QD剂量下观察到几乎完全抑制。在较高剂量下清楚地显示出肿瘤消退。所有其他体外和体内PK和安全性测试均显示出良好的结果，并支持PH027-1的临床前开发。参考文献2024AACR摘要https://www.abstractsonline.com/pp8/#!/20272

AACR会议临床1期临床结果