Truncating Mutation in the Autophagy Gene \u3cem\u3eUVRAG\u3c/em\u3e Confers Oncogenic Properties and Chemosensitivity in Colorectal Cancers

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAGFS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAGFS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAGFS can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAGFS expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response

مقایسه یادگیری حرکتی صریح و یادگیری حرکتی ضمنی در کودکان مبتلا به اوتیسم با عملکرد بالا و آسپرگر با همتایان عادی

مقدمه: اختلالات طیف اوتیسم با ناهنجاری‌های مناطق قشری همراه می‌باشند که پایه‌ای برای نقص یادگیری حرکتی ایجاد کرده‌اند. یادگیری حرکتی به دو طبقه اصلی صریح و ضمنی تقسیم می‌شود. هدف این پژوهش، تعیین تفاوت یادگیری حرکتی صریح با ضمنی و میزان تحکیم یادگیری بعد از 24 ساعت در پسران مبتلا به اختلالات طیف اوتیسم و همتایان عادی بود. مواد و روش‌ها: در این مطالعه، 30 پسر مبتلا به اختلالات طیف اوتیسم با 32 پسر همتای عادی مقایسه شدند. نمونه‌های سالم و مبتلا به اختلالات طیف اوتیسم با استفاده از تست ASSQ     از دبستان‌های پسرانه شهرستان نجف آباد انتخاب گردیدند. هر دو گروه در روز اول به انجام آزمون زمان عکس‌العمل متوالی (10 بلوک) با دست راست پرداختند و روز بعد، آزمون را در 4 بلوک به منظور سنجش تحکیم انجام دادند. آزمون ANOVA با اندازه‌گیری مکرر و با استفاده از 19SPSS جهت تحلیل داده‌ها مورد استفاده قرار گرفت. یافته‌ها: دو گروه در موضوع یادگیری صریح تفاوت معنی‌داری با یکدیگر داشتند که بیانگر نقص یادگیری صریح در افراد مبتلا به اختلالات طیف اوتیسم بود (009/0 = P). نتایج همچنین عدم تفاوت معنی‌دار را در یادگیری ضمنی بین دو گروه نشان داد (385/0 = P)، به علاوه یافته‌ها حاکی از این است که تحکیم یادگیری ضمنی در گروه اختلالات طیف اوتیسم (160/0 = P) نیز بی‌نقص و تحکیم یادگیری صریح دچار اختلال (046/0 = P) می‌باشد. نتیجه‌گیری: نقص یادگیری حرکتی صریح و تحکیم آن در گروه اختلالات طیف اوتیسم می‌تواند به علت اختلال عملکرد نیمکره چپ، تخصصی شده در یادگیری صریح، باشد. به علاوه تحکیم یادگیری صریح وابسته به خواب است و در گروه اختلالات طیف اوتیسم اختلالات خواب وجود دارد، بنابراین این نقص دور از انتظار نیست. سالم بودن یادگیری ضمنی و تحکیم آن را نیز می‌توان به تأثیر نیمکره راست در یادگیری حرکتی ضمنی نسبت داد. کلمات کلیدی: یادگیری حرکتی، یادگیری صریح، یادگیری ضمنی، اوتیسم با عملکرد بالا، آسپرگر، اختلالات خواب، آزمون زمان عکس‌العمل متوالی، تحکیم 

Diversification in the mountains: Evolutionary history and molecular phylogeny of Anatolian rock lizards

© 2022Mountains play a key role in forming biodiversity by acting both as barriers to gene flow among populations and as corridors for the migration of populations adapted to the conditions prevailing at high elevations. The Anatolian and the Zagros Mountains are located in the Alpine-Himalayan belt. The formation of these mountains has influenced the distribution and isolation of the animal population since the late Cenozoic. Apathya is a genus of lacertid lizards distributed along these mountains with two species, i.e., Apathya cappadocica and Apathya yassujica. The taxonomy status of lineages within the genus is complicated. In this study, we tried to collect extensive samples from throughout the distribution range, especially within the Zagros Mountains. Also, we used five genetic markers, two mitochondrial (COI and Cyt b) and three nuclear (C-mos, NKTR, and MCIR), to resolve the phylogenetic relationships within the genus and explain several possible scenarios that shaped multiple genetic structures. The combination of results in the current study indicated eight well-support monophyletic lineages that separated to two main groups; group 1 including A. c. cappadocica, A. c. muhtari and A. c. wolteri, group 2 contains four regional clades Turkey, Urmia, Baneh and Ilam, and finally a single clade belonging to the species A. yassujica. In contrast to previous studies, Apathya cappadocica urmiana was divided into four clades and three clades were recognized within Iranian boundaries. The clades have dispersed from Anatolia to adjacent regions in the south of Anatolia and the western Zagros Mountains. According to the evidence generated in this study this clade is paraphyletic. Based on our assumption, orogeny activities and also climate fluctuations in Middle Miocene and Pleistocene have influenced to formation of lineages. In this study we revisit the taxonomy of the genus and demonstrate that the species diversity was substantially underestimated. Our findings suggest that each of the eight clades corresponding to subspecies and distinct geographic regions deserve to be promoted to species level

Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase.

UV-induced DNA damage, a major risk factor for skin cancers, is primarily repaired by nucleotide excision repair (NER). UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy. It was initially isolated as a cDNA partially complementing UV sensitivity in xeroderma pigmentosum (XP), but this was not explored further. Here we show that UVRAG plays an integral role in UV-induced DNA damage repair. It localizes to photolesions and associates with DDB1 to promote the assembly and activity of the DDB2-DDB1-Cul4A-Roc1 (CRL4(DDB2)) ubiquitin ligase complex, leading to efficient XPC recruitment and global genomic NER. UVRAG depletion decreased substrate handover to XPC and conferred UV-damage hypersensitivity. We confirmed the importance of UVRAG for UV-damage tolerance using a Drosophila model. Furthermore, increased UV-signature mutations in melanoma correlate with reduced expression of UVRAG. Our results identify UVRAG as a regulator of CRL4(DDB2)-mediated NER and suggest that its expression levels may influence melanoma predisposition

Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase.

UV-induced DNA damage, a major risk factor for skin cancers, is primarily repaired by nucleotide excision repair (NER). UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy. It was initially isolated as a cDNA partially complementing UV sensitivity in xeroderma pigmentosum (XP), but this was not explored further. Here we show that UVRAG plays an integral role in UV-induced DNA damage repair. It localizes to photolesions and associates with DDB1 to promote the assembly and activity of the DDB2-DDB1-Cul4A-Roc1 (CRL4(DDB2)) ubiquitin ligase complex, leading to efficient XPC recruitment and global genomic NER. UVRAG depletion decreased substrate handover to XPC and conferred UV-damage hypersensitivity. We confirmed the importance of UVRAG for UV-damage tolerance using a Drosophila model. Furthermore, increased UV-signature mutations in melanoma correlate with reduced expression of UVRAG. Our results identify UVRAG as a regulator of CRL4(DDB2)-mediated NER and suggest that its expression levels may influence melanoma predisposition