14,441 research outputs found
A study on the correlation of nucleotide skews and the positioning of the origin of replication: different modes of replication in bacterial species
Deviations from Chargaff's 2nd parity rule, according to which A∼T and G∼C in single stranded DNA, have been associated with replication as well as with transcription in prokaryotes. Based on observations regarding mainly the transcription-replication co-linearity in a large number of prokaryotic species, we formulate the hypothesis that the replication procedure may follow different modes between genomes throughout which the skews clearly follow different patterns. We draw the conclusion that multiple functional sites of origin of replication may exist in the genomes of most archaea and in some exceptional cases of eubacteria, while in the majority of eubacteria, replication occurs through a single fixed origin
Core promoter: A critical region where the hepatitis B virus makes decisions
The core promoter (CP) of the viral genome plays an important role for hepatitis B virus (HBV) replication as it directs initiation of transcription for the synthesis of both the precore and pregenomic (pg) RNAs. The CP consists of the upper regulatory region and the basal core promoter (BCP). The CP overlaps with the 3’-end of the X open reading frames and the 5’-end of the precore region, and contains cis-acting elements that can independently direct transcription of the precore mRNA and pgRNA. Its transcription regulation is under strict control of viral and cellular factors. Even though this regulatory region exhibits high sequence conservation, when variations appear, they may contribute to the persistence of HBV within the host, leading to chronic infection and cirrhosis, and eventually, hepatocellular carcinoma. Among CP sequence variations, those occurring at BCP may dysregulate viral gene expression with emphasis in the hepatitis B e antigen, and contribute to disease progression. In this review these molecular aspects and pathologic topics of core promoter are deeply evaluated.Fil: Quarleri, Jorge Fabian. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin
Pervasive lesion segregation shapes cancer genome evolution
Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, quantification of oncogenic selection, and fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.This work was supported by: Cancer Research UK (20412, 22398), the European Research Council (615584, 682398), the Wellcome Trust (WT108749/Z/15/Z, WT106563/Z/14/A, WT202878/B/16/Z), the European Molecular Biology Laboratory, the MRC Human Genetics Unit core funding programme grants (MC_UU_00007/11, MC_UU_00007/16), and the ERDF/Spanish Ministry of Science, Innovation and Universities-Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00)
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Mapping the Genomic Context of Mutagenesis
The accumulation of genomic mutations leads to the formation of cancer. For this reason, many efforts have been undertaken to characterise mutational processes in terms of their genomic imprints. A particularly successful approach is matrix-based mutational signature analysis, which identifies prototypical mutation patterns by applying non-negative matrix factorisation to catalogues of single nucleotide variants and other mutation types. However, mutagenesis is a multifaceted event that is affected by the genomic organisation of DNA and cellular processes such as transcription, replication, and DNA repair processes. Moreover, since many mutational processes also generate characteristic multi nucleotide variants, insertion and deletions, and structural variants, it appears valuable to jointly deconvolve broader mutational catalogues to better understand the complex nature of mutagenesis.
In this thesis, I present TensorSignatures, an algorithm to learn mutational signatures jointly across different variant categories as well as their genomic localisation and properties. The analysis of 2,778 primary and 3,824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that practically all signatures operate dynamically in response to various genomic and epigenomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis, which is detected in 7 different cancer types. The algorithm also extracts distinct signatures of replication- and double strand break repair-driven mutagenesis by APOBEC3A and 3B with differential numbers and length of mutation clusters. As a fourth example, TensorSignatures reproduces a signature of somatic hypermutation generating highly clustered variants around the transcription start sites of active genes in lymphoid leukaemia, distinct from a more general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types. Finally, I demonstrate TensorSignatures’ utility by applying it to multiple datasets in various collaboration projects.
Taken together, TensorSignatures adds great detail and refines mutational signature analysis by jointly learning mutation patterns and their genomic determinants. This sheds light on the manifold influences that underlie mutagenesis and helps to pinpoint mutagenic influences which cannot easily be distinguished based on the mutation spectra alone. As mutational signature analysis is an essential element of the cancer genome analysis toolkit, TensorSignatures may help make the growing catalogues of mutational signatures more insightful by highlighting mutagenic mechanisms, or hypotheses thereof, to be investigated in greater depth
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Genomic Alteration Burden in Advanced Prostate Cancer and Therapeutic Implications.
The increasing number of patients with sequenced prostate cancer genomes enables us to study not only individual oncogenic mutations, but also capture the global burden of genomic alterations. Here we review the extent of tumor genome mutations and chromosomal structural variants in various clinical states of prostate cancer, and the related prognostic information. Next, we discuss the underlying mutational processes that give rise to these various alterations, and their relationship to the various molecular subtypes of prostate cancer. Finally, we examine the relationships between the tumor mutation burden of castration-resistant prostate cancer, DNA repair defects, and response to immune checkpoint inhibitor therapy
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