Spring Conference 2011 - Society for General Microbiology

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Please note: Abstracts are published as received from the authors and are not subject to editing. 37 Spring Meeting 11–14 April 2011 Harrogate – www.sgmharrogate2011.org.uk SESSION AbSTrACTS HA07 Mechanisms of DNA repair ↑Contents DNA repair in pathogenesis of tubercle bacilli Jaroslaw Dziadek Institute for Medical Biology, Polish Academy of Sciences, Lodz, Poland Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis is exposed to a range of environmental insults, including the host’s immune response, during the infectious process. From the moment MTB are exhaled by infected individuals, through an active and latent phase in the body of a new host, till the time they reach the reactivation stage, MTB are exposed to many types of DNA damaging agents. like all cellular organisms, MTB have efficient DNA repair systems, and these are believed to play essential roles in mycobacterial pathogenesis. As different stages of infection have great variation in the conditions in which mycobacteria reside, it is possible that different repair systems would be essential for progression to specific phases of infection. DNA double-strand breaks (DSBs), are the most lethal type of lesion that the genome can experience, as even a single unrepaired break can result in cell death. The DSBs in mycobacteria have to be repaired by homologous recombination (Hr) or non-homologous end-joining (NHEJ) DNA repair pathways. The role of ATPdependent ligases in the DSBs repair process and the essentiality of NHEJ and Hr in the early step of infection were investigated. DNA damage response in the archaeon Haloferax volcanii: the role of Mre11-rad50 Stéphane Delmas, THOrSTEN AllErS School of Biology, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH in polyploid species, the presence of multiple genome copies has profound implications for strategies of DNA repair. We studied DNA repair in the halophilic archaeon Haloferax volcanii, which maintains up to 20 genome copies. We have focussed on the Mre11-rad50 complex, it is present in all domains of life and it plays a central role in the eukaryotic DNA damage response. Our results indicate that Mre11-rad50 play several roles in the DNA damage response of H. volcanii. On the one hand, it delays the use of homologous recombination, instead favouring micro-homology mediated end joining as an initial means of DNA double-strand break repair. On the other hand, Mre11-rad50 reorganizes the structure on the nucleoid in response to DNA damage, compacting genomic DNA inside the cytoplasm. We propose that the nucleoid compaction is part of the DNA damage response, in order to accelerate the localization of target sequences by DNA repair proteins. We suggest that polyploidy organisms use a DNA damage response that minimises the use of homologous recombination, since this repair strategy has the potential to create branched DNA structures that can prove difficult to resolve. removal of covalently bound topoisomerases from DNA by MrN and Ctp1 Edgar Hartsuiker NWCRF Institute, School of Biological Sciences, Bangor University Camptothecins (CPTs) and etoposides are important cancer drugs which trap topoisomerases on the DNA. For a (cancer) cell to survive treatment the topoisomerases need to be removed. We have recently shown that the Schizosaccharomyces pombe rad32Mre11 nuclease activity is involved in the removal of both rec12Spo11 and Top2 from 5’ DNA ends, as well as Top1 from 3’ ends in vivo. A ctp1CtiP deletion is defective for rec12Spo11 and Top2 removal but over-proficient for Top1 removal, suggesting that Ctp1CtiP plays distinct roles in removing topoisomerases from 5’ and 3’ DNA ends. Analysis of separation of function mutants suggests that MrN-dependent topoisomerase removal contributes significantly to resistance against topoisomerase-trapping drugs. We have recently obtained preliminary evidence that the rad32Mre11 nuclease activity is also involved in providing resistance to another clinically important group of cancer drugs, the nucleoside analogues. These studies have important implications for our understanding of the role of the MrN complex and CtiP in resistance of cells to clinically important cancer drugs. Yeast global genome nucleotide excision repair promotes chromatin remodelling required for efficient repair of UV-induced DNA damage SiMON rEED, Shirong Yu, Yumin Teng, Mark Bennett, raymond Waters Dept of Medical Genetics, Haematology & Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN Following uV radiation induced DNA damage, increased histone H3 acetylation at lysine 9 and 14 correlates with changes in chromatin structure and these alterations are associated with efficient global genome nucleotide excision repair (GG-NEr) in yeast. Both these changes occur in response to uV radiation in the absence of functional GG-NEr. recently we reported that although these changes HA07 ↑Contents s o c i e t y f o r g e n e r a l Microbiology
Please note: Abstracts are published as received from the authors and are not subject to editing. 38 Spring Meeting 11–14 April 2011 Harrogate – www.sgmharrogate2011.org.uk SESSION AbSTrACTS ↑Contents HA07 Cont. occur independently of functional NEr, they do depend on the rad16 GG-NEr protein. remarkably, we showed that constitutive hyperacetylation of histone H3 can suppress the requirement for both the rad7 and rad16 GG-NEr proteins during DNA repair. These observations hinted at a possible mechanistic link between the rad7 and rad16 proteins and the process of chromatin remodelling required for efficient DNA repair. Here we reveal how uV induced histone H3 acetylation is regulated during GG-NEr, and how this promotes chromatin remodeling necessary for efficient repair of DNA damage. We show that yeast rad7 and rad16 proteins drive uV induced chromatin remodelling by controlling histone H3 acetylation levels in chromatin. This is achieved via the concerted action of the ATPase, and C3HC4 riNG domains of rad16, which in concert regulate the occupancy of histone acetyl transferases on chromatin in response to uV damage. Offered paper Archaeal DNA repair helicase Hel308: structure–function and interactions with proteins of DNA replication and recombination isabel Woodman, Kirsty Brammer, EDWArD BOlT University of Nottingham, Nottingham Hel308 is an archaeal super-family 2 helicase with homologues in higher eukaryotes involved in repair of DNA strand crosslinks. Contributions of Hel308 to DNA repair processes are far from clear, including how it co-operates with other proteins. using archaeal Hel308 we identified physical interaction with rPA that required a conserved amino acid motif at the Hel308 C-terminus1 . This and previous analyses of Hel308 led us to propose that in archaea rPA acts as a platform for loading of Hel308 onto aberrant single-stranded DNA (ssDNA) arising at blocked replication forks. in line with data from a human Hel308 homologue, the helicase activity of archaeal Hel308 was only modestly stimulated by rPA, much less so than for other known interactions between helicases and ssDNA binding proteins. This supports a model for rPA localizing Hel308 to DNA damage sites, rather than stimulating the mechanism of helicase unwinding. We also present details of a winged helix domain structure in Hel308 that is conserved in rNA remodelling proteins Brr2, Mtr4 and Prp43p, and that may function to maintain structural integrity of the overall Hel308 ring structure, and engages with nucleic acid. References: (1). Woodman il, Brammer K and Bolt El (2010) DNA repair. doi:10.1016/j.dnarep.2010.12.001 Extreme gene machines: maintaining genetic integrity in boiling acid Malcolm F. White University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST Archaea frequently inhabit extreme environments and thus face challenges in maintaining functional cellular structures and macromolecules, in particular DNA and proteins. This evolutionary pressure has resulted in many adaptations that overlay the fundamental relationship between the archaea and eukarya in information processing systems. This talk will focus on recent research in our laboratory on the Nucleotide Excision repair (NEr) pathway in the model crenarchaeon Sulfolobus solfataricus, which grows in volcanic pools at 80°C, pH3. NEr removes bulky lesions such as photoproducts from DNA. lesions are detected, DNA unwound locally and nicks introduced on either side of the damage to release an oligonucleotide ‘patch’ containing the damage. The gapped product is then repaired by DNA synthesis. The enzymatic components of eukaryal NEr are the xPB and xPD helicases (components of transcription factor TFiiH) and the xPF and xPG nucleases. Most archaea have clear homologues of xPB, xPD and xPF, and these have been presumed to function in an NEr pathway that resembles a simplified version of the eukaryal process. recent work exploring the structures and mechanisms of the archaeal proteins will be discussed. The ends are nigh: proteins involved in binding to DNA ends in streptomycetes richard P. Bowater School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ To maintain genomic integrity, all cells contain a variety of pathways that specialise in the repair and removal of particular damage-induced DNA lesions. DNA double-strand breaks (DSBs) are especially toxic to cells and different pathways act to ensure these are repaired. Nonhomologous end joining (NHEJ) is one pathway used to repair DSBs and it has been well characterized in eukaryotes. Homologous genes are present in a range of prokaryotes, and a functional NHEJ pathway has been confirmed in mycobacteria, where it is coordinated by two gene products. The bacterium Streptomyces coelicolor is an actinomycete with a complex life cycle, and it has homologues to the genes for mycobacterial NHEJ, but the biochemical activities for NHEJ appear to be encoded by at least 5 different genes. We have cloned the relevant genes and purified recombinant versions of the proteins, which include several DNA ligases, multiple Ku (end-binding) proteins, a nuclease and several primases. Preliminary experiments confirm that these proteins possess the expected biochemical activities in terms s o c i e t y f o r g e n e r a l Microbiology
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Spring Conference 2011 - Society for General Microbiology

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