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Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.
Arai, H, Xiao, Y, Millstein, J, Wang, J, Battaglin, F, Kawanishi, N, Jayachandran, P, Soni, S, Zhang, W, Mancao, C, et al
British journal of cancer. 2022;(1):72-78
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Abstract
BACKGROUND The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). METHODS We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. RESULTS In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. CONCLUSIONS TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.
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Zinc finger proteins in the host-virus interplay: multifaceted functions based on their nucleic acid-binding property.
Wang, G, Zheng, C
FEMS microbiology reviews. 2021;(3)
Abstract
Zinc finger proteins (ZFPs) are a huge family comprised of massive, structurally diverse proteins characterized by zinc ion coordinating. They engage in the host-virus interplay in-depth and occupy a significant portion of the host antiviral arsenal. Nucleic acid-binding is the basic property of certain ZFPs, which draws increasing attention due to their immense influence on viral infections. ZFPs exert multiple roles on the viral replications and host cell transcription profiles by recognizing viral genomes and host mRNAs. Their roles could be either antiviral or proviral and were separately discussed. Our review covers the recent research progress and provides a comprehensive understanding of ZFPs in antiviral immunity based on their DNA/RNA binding property.
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Spanning the gap: unraveling RSC dynamics in vivo.
Neumann, H, Wilkins, BJ
Current genetics. 2021;(3):399-406
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Abstract
Multiple reports over the past 2 years have provided the first complete structural analyses for the essential yeast chromatin remodeler, RSC, providing elaborate molecular details for its engagement with the nucleosome. However, there still remain gaps in resolution, particularly within the many RSC subunits that harbor histone binding domains.Solving contacts at these interfaces is crucial because they are regulated by posttranslational modifications that control remodeler binding modes and function. Modifications are dynamic in nature often corresponding to transcriptional activation states and cell cycle stage, highlighting not only a need for enriched spatial resolution but also temporal understanding of remodeler engagement with the nucleosome. Our recent work sheds light on some of those gaps by exploring the binding interface between the RSC catalytic motor protein, Sth1, and the nucleosome, in the living nucleus. Using genetically encoded photo-activatable amino acids incorporated into histones of living yeast we are able to monitor the nucleosomal binding of RSC, emphasizing the regulatory roles of histone modifications in a spatiotemporal manner. We observe that RSC prefers to bind H2B SUMOylated nucleosomes in vivo and interacts with neighboring nucleosomes via H3K14ac. Additionally, we establish that RSC is constitutively bound to the nucleosome and is not ejected during mitotic chromatin compaction but alters its binding mode as it progresses through the cell cycle. Our data offer a renewed perspective on RSC mechanics under true physiological conditions.
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Progressive sector retinitis pigmentosa due to c.440G>T mutation in SAG in an Australian family.
Pappalardo, J, Heath Jeffery, RC, Thompson, JA, Charng, J, Chelva, ES, Constable, IJ, McLaren, TL, Lamey, TM, De Roach, JN, Chen, FK
Ophthalmic genetics. 2021;(1):62-70
Abstract
BACKGROUND Heterozygous c.440 G > T mutation in the S-antigen visual arrestin (SAG) gene has been described as a cause of autosomal dominant retinitis pigmentosa (adRP) in a series of patients of Hispanic origin. This study presents the early and late clinical features and disease progression rates in an Australian family with SAG adRP. MATERIALS AND METHODS An observational case series of four family members with adRP. They were examined clinically, with multi-modal retinal imaging and electroretinography (ERG) to ascertain phenotype. Disease progression rate was measured using optical coherence tomography (OCT) and fundus autofluorescence (FAF). A retinal dystrophy panel was used for the proband and cascade testing with targeted Sanger sequencing was conducted in other available family members. RESULTS The proband presented at 36 years of age with profoundly reduced full-field ERG responses despite a sector RP phenotype. This progressed to a classic RP pattern over several decades leaving a small residual island of central visual field. The horizontal span of the residual outer nuclear layer and the area of hyperautofluorescent ring contracted at a rate of 8-11% and 9-14% per year, respectively. DNA sequencing confirmed the segregation of SAG c.440 G > T mutation with disease. CONCLUSION SAG adRP presents with a reduced full-field ERG response consistent with a rod-cone dystrophy in mid-life despite a sector RP phenotype. Centripetal progression of the disease into the macula can be tracked by OCT and FAF imaging.
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Vitamin D related genetic polymorphisms affect serological response to high-dose vitamin D supplementation in multiple sclerosis.
Mimpen, M, Rolf, L, Poelmans, G, van den Ouweland, J, Hupperts, R, Damoiseaux, J, Smolders, J
PloS one. 2021;(12):e0261097
Abstract
INTRODUCTION A poor 25-hydroxyvitamin D (25(OH)D) status is a much replicated risk factor for developing multiple sclerosis (MS), and several vitamin D-associated single nucleotide polymorphisms (SNPs) have been associated with a higher risk of MS. However, studies on the benefit of vitamin D supplementation in MS show inconclusive results. Here, we explore whether vitamin D-associated SNPs and MS risk alleles confound serological response to vitamin D supplementation. METHODS 34 participants from the SOLARIUM study consented to genotyping, of which 26 had vitamin D data available. The SOLARIUM study randomised relapsing-remitting MS patients to placebo or 14,000 IU vitamin D3 for 48 weeks. Participants were categorised as either 'carriers' or 'non-carriers' of the risk allele for 4 SNPs: two related to D binding protein (DBP) and associated with lower 25(OH)D levels (rs4588 and rs7041), and two related to vitamin D metabolism enzymes CYP27B1 and CYP24A1 and associated with a higher risk of MS (rs12368653; rs2248359, respectively). 25(OH)D levels were determined at baseline and after 48 weeks. RESULTS The DBP-related SNPs showed no difference in 25(OH)D status at baseline, but carriers of the rs7041 risk allele showed lower 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 224.2 vs. 332.0 nmol/L, p = 0.013). For CYP related SNPs, neither showed a difference at baseline, but carriers of the rs12368653 risk allele showed higher 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 304.1 vs. 152.0 nmol/L, p = 0.014). DISCUSSION Vitamin D-related SNPs affect the serological response to high-dose vitamin D supplementation. The effects on more common doses of vitamin D, as well as the clinical consequence of this altered response, need to be investigated further.
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Identifying DNA-binding proteins based on multi-features and LASSO feature selection.
Zhang, S, Zhu, F, Yu, Q, Zhu, X
Biopolymers. 2021;(2):e23419
Abstract
DNA-binding proteins perform an indispensable function in the maintenance and processing of genetic information and are inefficiently identified by traditional experimental methods due to their huge quantities. On the contrary, machine learning methods as an emerging technique demonstrate satisfactory speed and accuracy when used to study these molecules. This work focuses on extracting four different features from primary and secondary sequence features: Reduced sequence and index-vectors (RS), Pseudo-amino acid components (PseAACS), Position-specific scoring matrix-Auto Cross Covariance Transform (PSSM-ACCT), and Position-specific scoring matrix-Discrete Wavelet Transform (PSSM-DWT). Using the LASSO dimension reduction method, we experiment on the combination of feature submodels to obtain the optimized number of top rank features. These features are respectively input into the training Ensemble subspace discriminant, Ensemble bagged tree and KNN to predict the DNA-binding proteins. Three different datasets, PDB594, PDB1075, and PDB186, are adopted to evaluate the performance of the as-proposed approach in this work. The PDB1075 and PDB594 datasets are adopted for the five-fold cross-validation, and the PDB186 is used for the independent experiment. In the five-fold cross-validation, both the PDB1075 and PDB594 show extremely high accuracy, reaching 86.98% and 88.9% by Ensemble subspace discriminant, respectively. The accuracy of independent experiment by multi-classifiers voting is 83.33%, which suggests that the methodology proposed in this work is capable of predicting DNA-binding proteins effectively.
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Novel GRHL2 Gene Variant Associated with Hearing Loss: A Case Report and Review of the Literature.
Trebusak Podkrajsek, K, Tesovnik, T, Bozanic Urbancic, N, Battelino, S
Genes. 2021;(4)
Abstract
In contrast to the recessive form, hearing loss inherited in a dominant manner is more often post-lingual and typically results in a progressive sensorineural hearing loss with variable severity and late onset. Variants in the GRHL2 gene are an extremely rare cause of dominantly inherited hearing loss. Genetic testing is a crucial part of the identification of the etiology of hearing loss in individual patients, especially when performed with next-generation sequencing, enabling simultaneous analysis of numerous genes, including those rarely associated with hearing loss. We aimed to evaluate the genetic etiology of hearing loss in a family with moderate late-onset hearing loss using next-generation sequencing and to conduct a review of reported variants in the GRHL2 gene. We identified a novel disease-causing variant in the GRHL2 gene (NM_024915: c.1510C>T; p.Arg504Ter) in both affected members of the family. They both presented with moderate late-onset hearing loss with no additional clinical characteristics. Reviewing known GRHL2 variants associated with hearing loss, we can conclude that they are more likely to be truncating variants, while the associated onset of hearing loss is variable.
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Redox-mediated regulation of low complexity domain self-association.
Kato, M, Tu, BP, McKnight, SL
Current opinion in genetics & development. 2021;:111-118
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Abstract
Eukaryotic cells express thousands of protein domains long believed to function in the absence of molecular order. These intrinsically disordered protein (IDP) domains are typified by gibberish-like repeats of only a limited number of amino acids that we refer to as domains of low sequence complexity. A decade ago, it was observed that these low complexity (LC) domains can undergo phase transition out of aqueous solution to form either liquid-like droplets or hydrogels. The self-associative interactions responsible for phase transition involve the formation of specific cross-β structures that are unusual in being labile to dissociation. Here we give evidence that the LC domains of two RNA binding proteins, ataxin-2 and TDP43, form cross-β interactions that specify biologically relevant redox sensors.
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Genetics and Pathogenetic Role of Inflammasomes in Philadelphia Negative Chronic Myeloproliferative Neoplasms: A Narrative Review.
Di Battista, V, Bochicchio, MT, Giordano, G, Napolitano, M, Lucchesi, A
International journal of molecular sciences. 2021;(2)
Abstract
The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.
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Role of ZBTB7A zinc finger in tumorigenesis and metastasis.
Singh, AK, Verma, S, Kushwaha, PP, Prajapati, KS, Shuaib, M, Kumar, S, Gupta, S
Molecular biology reports. 2021;(5):4703-4719
Abstract
The zinc finger and BTB (broad-complex, tramtrack and bric a brac) domain containing protein 7A (ZBTB7A) is a pleiotropic transcription factor that plays an important role in various stages of cell proliferation, differentiation, and other developmental processes. ZBTB7A is a member of the POK family that directly and specifically binds to short DNA recognition sites located near their target genes thereby acting as transcriptional activator or repressor. ZBTB7A overexpression has been associated with tumorigenesis and metastasis in various human cancer types, including breast, prostate, lung, ovarian, and colon cancer. However in some instances downregulation of ZBTB7A results in tumor progression, suggesting its role as a tumor suppressor. ZBTB7A is involved with complicated regulatory networks which include protein-protein and protein-nucleic acid interactions. ZBTB7A involvement in cancer progression and metastasis is perhaps enabled through the regulation of various signaling pathways depending on the type and genetic context of cancer. The association of ZBTB7A with other proteins affects cancer aggressiveness, therapeutic resistance and clinical outcome. This review focuses on the involvement of ZBTB7A in various signaling pathways and its role in cancer progression. We will also review the literature on ZBTB7A and cancer which could be potentially explored for its therapeutic implications.