Title: Structure of hepadnaviral pre-genomic RNA. We aim to study the replication strategy of human hepatitis B virus (HBV), a member of the hepadnavirus family. Hepadnaviruses infect hepatocytes in the liver and are released in high numbers into the bloodstream. Infection is transmitted by blood or sexual contact. Hepadnaviruses cause acute and chronic infection with varying degrees of liver disease. The HBV DNA genome is formed by copying of a viral pre-genome made of RNA, into DNA. This proce ....Title: Structure of hepadnaviral pre-genomic RNA. We aim to study the replication strategy of human hepatitis B virus (HBV), a member of the hepadnavirus family. Hepadnaviruses infect hepatocytes in the liver and are released in high numbers into the bloodstream. Infection is transmitted by blood or sexual contact. Hepadnaviruses cause acute and chronic infection with varying degrees of liver disease. The HBV DNA genome is formed by copying of a viral pre-genome made of RNA, into DNA. This process is called reverse transcription and is performed by the viral polymerase. Reverse transcription occurs within viral nucleocapsids made of core antigen. After formation of the new viral DNA genome, nucleocapsids are enveloped in surface antigen and are released from the cell. It is assumed that 1 copy of HBV pre-genomic RNA is packaged within each viral nucleocapsid. However, members of the retrovirus family that have common evolutionary origins to hepadnaviruses and also replicate via reverse transcription, contain 2 copies of RNA. The human immunodeficiency virus (HIV), the AIDS virus, is a well-studied example. In HIV infection 2 RNA genomes are packaged into each nucleocapsid and form a dimeric RNA genome. The HIV RNA is able to fold into a series of stem loops that promote formation of dimers. During the reverse transcription step in HIV replication, the polymerase switches templates and forms new combined strains of virus. The project aims to determine if 2 copies of pre-genomic RNA are packaged into HBV nucleocapsids. HBV pre-genomic RNA is able to form stem loop structures similar to those in HIV and has the potential to form dimeric RNA. If 2 copies of HBV pre-genomic RNA are packaged this will allow us to redefine the viral replication strategy and to develop a greater understanding of the relationships between hepadnaviruses and retroviruses. The formation of dimers will also provide a mechanism for recombination between HBV strains.Read moreRead less
Role Of DNA Methylation And Non-coding RNA In Human Centromere Function
Funder
National Health and Medical Research Council
Funding Amount
$499,000.00
Summary
A chromosome is a grouping of coiled strands of DNA, containing many genes. Every human cell has 23 pairs of chromosomes, which together comprise the genome. Both gain and loss of any of these chromosomes will lead to severe medical problems including birth defects and cancer development. Thus, the understanding of the mechanisms underlying the exact passage of these chromosomes from a parental cell to two new cells during cell division, and how the information is copied from from one cell gener ....A chromosome is a grouping of coiled strands of DNA, containing many genes. Every human cell has 23 pairs of chromosomes, which together comprise the genome. Both gain and loss of any of these chromosomes will lead to severe medical problems including birth defects and cancer development. Thus, the understanding of the mechanisms underlying the exact passage of these chromosomes from a parental cell to two new cells during cell division, and how the information is copied from from one cell generation to another, is an important area of research, however, much remains to be learnt about the mechanisms. Our laboratory was the first to discover a key component of the chromosome that is involved in the regulation of the cell division process, ensuring the accurate segregation of chromosomes. This structure, known as a neocentromere, is an ideal model system to study important aspects of chromosome segregation. The present project proposes to study the properties of this neocentromere in detail. The outcome will contribute to our knowledge on the processes underlying cell and chromosome division, which will ultimately have a direct impact on our understanding of the causes for some of the most common clinical conditions that affect human health.Read moreRead less
Dnmt3L Haploinsufficent Retrotransposition Leads To Genetic Hypermutation
Funder
National Health and Medical Research Council
Funding Amount
$613,982.00
Summary
This project aims to demonstrate the critical importance of DNA methylation as a cause of mutation and thus genetic diseases, many instances of sterility and low fertility, and cancers. Because DNA methylation can be partially determined by substrate availability, a demonstration of the importance of DNA methylation vis a vis mutation rates will refine our understanding of the impact of metabolism and nutrition on mutation rate as a cause of human disease.
Pathways That Regulate Nuclear Export Of Circular RNA
Funder
National Health and Medical Research Council
Funding Amount
$933,327.00
Summary
An emerging and unusual class of RNA molecules, circular RNAs (circRNAs), is widespread and plays important roles in cancer initiation and progression. However, the pathways responsible for nuclear export of circRNAs are unknown. We propose here to systematically determine how circRNAs are exported from the nucleus and characterise the effect of modulating circRNA export pathways in cancer. This will enable us to determine whether circRNAs can function as a biomarker of patient response.
Alternative Splicing Of GLI1 And Its Role In Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$392,640.00
Summary
Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be transla ....Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be translated into a protein. One of these maturation steps involves the removal of sequences (called introns) that do not contain protein coding information from the sequences (called exons) that will be present in the mature mRNA. Some genes contain no introns while others contain 20 or more, which are dispersed throughout the gene. The removal of intron sequences from immature RNA molecules is called splicing and is carried out by a macromolecular complex that recognises the intron sequences, cuts them out of the RNA and then rejoins the RNA to make a contiguous sequence. This process has to be precise otherwise spurious sequences will be present in the mRNA, which will result in the production of abnormal proteins. In addition, for some genes mRNAs are produced that have differences in a portion of their sequence. These alternative sequences are generated by the inclusion or exclusion of alternative exons. Because, RNA splicing is critical to the production of mature mRNAs and because it can generate sequence diversity it is tightly regulated. We have recently found that expression of a cancer gene (called GLI1) is regulated in part by the use of alternative GLI1 mRNAs. Moreover, we found that the expression of one of these alternative GLI1 mRNAs is associated with skin cancer. In this project we will investigate the molecular mechanisms that regulate alternative splicing in GLI1 and identify whether changes in these mechanisms result in cancer.Read moreRead less
Investigating Deregulation Of Mitosis As A Mechanism Of Tumourigenesis In MYCN-driven Neuroblastoma
Funder
National Health and Medical Research Council
Funding Amount
$372,298.00
Summary
Neuroblastoma chemotherapy often only works temporarily because a small number of tumour cells can resist drugs and eventually regrow as a new tumour. These resistant cells resemble the very first cells that turn into a cancer cell at tumour initiation. We have used single cell technology to uncover genetic markers of tumour initiating cells. In this project we will determine how these marker genes cause tumour initiation and develop therapies that target them in drug resistant neuroblastoma.