Elucidating the mechanism of non-canonical DNA mismatch repair in mycobacteria View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2017-2020

FUNDING AMOUNT

729173 GBP

ABSTRACT

Our cells contain DNA, the so called "genetic blueprint of life", which encodes the information for all our genes. DNA has a simple repeating structure composed of two complementary strands of DNA composed of bases, which form long, string-like, double-helix structures that make up the genome. Our genome is packaged away into chromosomes, contained within the nucleus of nearly every cell. This information must be faithfully copied as cells divide to produce daughter cells. Cells produce a large number of proteins responsible for "photocopying" this DNA blueprint. The proteins tasked with accurately copying the several billion letters of our genetic code are called DNA replication polymerases. During this copying process, the replication machinery can introduce mutations to the newly made DNA sequence that can, if left unrepaired, lead to the development of disease states, such as cancer. Fortunately, our cells produce repair proteins whose role it is to remove the "mismatched" bases. We have recently discovered a novel bacterial repair gene called NucS and discovered that the protein it produces plays an important role in helping cells to excise mutations introduced during every round of cell division thus ensuring efficient genome replication. In this research programme, we are proposing to identify additional proteins that operate with NucS in the bacterial cell, determine how these repair machines are able to remove and correct DNA mutations, identify "when" and where" these complexes operate in cells, define the cellular consequences of deleting this repair pathway and, finally, determine if it co-operates with other repair pathways to ensure genome stability. This proposal will provide critical insights into a fundamental mutation avoidance pathway required to correct harmful genetic mismatch mutations that promote genetic instability. Excessive accumulation of mutations can lead to uncontrolled cell growth that can result in the onset of diseases, such as cancer. However, in prokaryotes it can lead to the development of antibiotic resistance in major pathogenic bacteria. The rise of antibiotic resistance has been identified as one of the major threats facing global health. Therefore, understanding fundamental mechanisms and pathways that influence mutation rates in bacteria will uncover new strategies to predict and combat the development of antibiotic resistance. Technical Summary Accurate replication of chromosomal DNA is vital to maintain genomic stability and preventing the accrual of genetic mutations. Cells ensure the maintenance of low DNA mutation rates using a combination of base selection, proofreading and mismatch repair mechanisms. Mismatch repair (MMR) is a sophisticated repair pathway that detects and removes incorrect mismatched bases. Loss of this pathway has important consequences, such as high rates of mutation and increased recombination between divergent DNA sequences. The MMR pathway is highly conserved among the three domains of life. However, most actinobacteria and archaea possess no identifiable MMR pathway but exhibit mutation rates similar to MMR-bearing species, suggesting the existence of unidentified mechanisms responsible for mismatch repair. We have identified a non-canonical MMR pathway in these organisms. Disruption of this repair pathway leads to hypermutation and the appearance of other genetic signatures associated with the loss of mismatch repair in other organisms. These results provide compelling evidence for the existence of an alternative MMR pathway in nature. The major aims of this proposal are to define the cellular factors required to perform non-canonical mismatch repair and elucidate the molecular mechanisms of non-canonical mismatch repair in mycobacteria. We will employ molecular and cellular approaches to provide complementary mechanistic insights into MMR and delineate how the MMR pathway operates to facilitate mutation avoidance. Together, these holistic studies will significantly enhance our understanding of how this non-canonical mutation correction system excises and repairs DNA mismatches in prokaryotic cells. It is also likely to provide critical insights into how such repair processes are associated with the development of antibiotic resistance in microbial pathogens. More... »

URL

http://gtr.rcuk.ac.uk/project/8D9FC97B-46B4-4E29-B6F7-C216B22FCE0D

Related SciGraph Publications

  • 2017-01-27. A non-canonical mismatch repair pathway in prokaryotes in NATURE COMMUNICATIONS
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