ABSTRACT
All living organisms need a DNA replication mechanism and it has been conserved in the three domains of life throughout evolutionary process. Primase is the enzyme responsible for synthesizing de novo RNA primers in DNA replication. Archaeo-Eukaryotic Primase (AEP) is the superfamily that typically forms a heterodimeric complex containing both a small catalytic subunit (PriS) and a large accessory noncatalytic subunit (PriL). Sulfolobus solfataricus is a model organism for research on the Genetics field. The aim of this work was to evaluate, via Bioinformatics tools, three mutations in the large subunit (PriL) of the archaeon Sulfolobus solfataricus. The aspartic acid residue in the positions (Asp) 62, (Asp) 235, (Asp) 241 have been substituted by glutamic acid (Glu). The highest positive free energy variation of the three substitutions analyzed occurred with the mutation at the (Asp) 241 site. The in silico analysis suggested that these mutations in PriL may destabilize its tridimensional structure interfering with replication mechanisms of Sulfolobus solfataricus. Moreover, it may also alter interactions with other molecules, making salt bridges, for instance.
Todos os organismos vivos necessitam de um eficiente mecanismo de replicação de DNA. Ao longo da evolução biológica foi observado que esse mecanismo é conservado nos três domínios da vida. Uma enzima importante que participa desse mecanismo é a RNA primase, a qual é responsável pela síntese de novo de iniciadores de RNA na replicação do DNA. Em Arquea-Eucariota, RNA Primase (AEP) tipicamente forma um complexo heterodimérico, que contém uma pequena subunidade catalítica (PriS) e uma subunidade maior não catalítica acessória (PriL). Sulfolobus solfataricus é um organismo modelo de Arquea para a pesquisa no campo da genética. O objetivo deste trabalho foi avaliar, por meio de ferramentas de bioinformática, três mutações pontuais na subunidade maior (PriL) de Sulfolobus solfataricus. Nas sequências mutantes, os resíduos de ácido aspártico nas posições (Asp) 62, (Asp) 235, (Asp) 241 foram substituídos por ácido glutâmico (Glu). A maior variação de energia livre positiva das três mutações analisadas ocorreu no sítio (Asp) 241. A análise in silico sugeriu que essas mutações em PriL podem desestabilizar sua estrutura tridimensional, interferindo com os mecanismos de replicação de Sulfolobus solfataricus. Além disso, podem alterar interações com outras moléculas, formando pontes salinas.
Subject(s)
Computer Simulation , DNA Replication Timing , Sulfolobus solfataricus , Mutation , RNA, Transfer, MetABSTRACT
Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs), are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability.
Subject(s)
Humans , Base Sequence , DNA , DNA Copy Number Variations , DNA Replication , DNA Replication Timing , Genome , Genome, Human , Genomic Instability , Mutagenesis , Recombination, GeneticABSTRACT
El virus de la hepatitis C (HCV) ha sido caracterizado en profundidad a nivel molecular en la última década. La partícula viral envuelta alberga una nucleocápside, estructura constituida principalmente por una proteína básica que está en estrecha interacción con el genoma viral representado por una molécula de ARN de cadena simple con polaridad positiva. La organización genómica del HCV es similar a la de Pestivirus y Flavivirus. Diferentes receptores celulares se han postulado en su participación para el ingreso del virus a la célula blanco. Su estrategia de multiplicación deja avizorar los blancos de acción de nuevas drogas para controlar la replicación. Si bien comparte con el HIV - desde su naturaleza de ARN virus - entre otras características virológicas la magnífica plasticidad genómica, otras por el contrario revisten claras diferencias. Ambos virus constituyen un enorme desafío en Salud
The hepatitis C virus (HCV) has been deeply characterized at molecular level during the last decade. The enveloped viral particle protects the nucleocapsid that is essentially constituted by a basic protein that interacts with the viral genome, a single strand RNA with positive polarity. The genomic organization of the HCV is similar to the Pestivirus and Flavivirus. Different cellular receptors have been postulated to play a role to the virus entry in the cellular target. The replication strategy exhibit the different plausible target of antiviral action with new drugs in order to control the replication. The HCV shares with the HIV the vast genomic plasticity because both are RNA viruses but other characteristics are different between them. Both viruses are an enormous trial for human health
Subject(s)
Humans , DNA Replication Timing , Genome, Viral/immunology , HIV , Hepacivirus/genetics , RNA , Virus Replication/immunology , Base Sequence/geneticsABSTRACT
Eukaryotic DNA replication is tightly restricted to only once per cell cycle in order to maintain genome stability. Cells use multiple mechanisms to control the assembly of the prereplication complex (pre-RC), a process known as replication licensing. This review focuses on the regulation of replication licensing by posttranslational modifications of the licensing factors, including phosphorylation, ubiquitylation and acetylation. These modifications are critical in establishing the pre-RC complexes as well as preventing rereplication in each cell cycle. The relationship between rereplication and diseases, including cancer and virus infection, is discussed as well.