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Le Touquet – Paris-Plage, France

Porcar M.,University of Valencia | Danchin A.,AMAbiotics SAS | de Lorenzo V.,CSIC - National Center for Biotechnology
BioEssays | Year: 2015

The emphasis of systems and synthetic biology on quantitative understanding of biological objects and their eventual re-design has raised the question of whether description and construction standards that are commonplace in electric and mechanical engineering are applicable to live systems. The tuning of genetic devices to deliver a given activity is generally context-dependent, thereby undermining the re-usability of parts, and predictability of function, necessary for manufacturing new biological objects. Tolerance (acceptable limits within the unavoidable divergence of a nominal value) and allowance (deviation introduced on purpose for the sake of flexibility and hence modularity, i.e. fitting together with a variety of other components) are key aspects of standardization that need to be brought to biological design. These should endow functional building blocks with a pre-specified level of confidence for bespoke biosystems engineering. However, in the absence of more fundamental knowledge, fine-tuning necessarily relies on evolutionary/combinatorial gravitation toward a fixed objective. © 2015 WILEY Periodicals, Inc.

Danchin A.,AMAbiotics SAS | Danchin A.,University of Hong Kong
FEBS Letters | Year: 2012

Using comparative genomics and functional analysis, this work summarises how the cell's genome is organised, with emphasis on the importance of the cell's chassis. Some discrete but important engineering constraints are reviewed, beginning with the need for scaffolds, as well as the question posed by the difficult task of putting a very long random thread (DNA) into a limited volume. Subsequently, to illustrate overlooked essential functions, we show the importance of safety valves, as well as the need to cope with leftovers. The third section discusses how transplantation experiments point out a remarkable feature of the cell factory: the program replicates (makes identical copies of itself), whereas the cell reproduces (makes similar copies of itself), placing in the limelight the role of informational maintenance. A final section identifies the need to put together a globally linear behaviour of the cell with intrisically non-linear genetic constructs. The discussion ends with the central question of evolvability of artificial constructs and to suggest that combining in vivo Synthetic Biology with biochemical reactors might be an efficient way forward. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Toledano E.,Institute Pasteur Paris | Ogryzko V.,Institute Gustave Roussy | Danchin A.,AMAbiotics SAS | Ladant D.,Institute Pasteur Paris | Mechold U.,Institute Pasteur Paris
Biochemical Journal | Year: 2012

pAp (3′-5′ phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the K m and the V max of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl) ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity. © The Authors Journal compilation © 2012 Biochemical Society.

Acevedo-Rocha C.G.,Max-Planck-Institut fur Kohlenforschung | Acevedo-Rocha C.G.,University of Marburg | Fang G.,Yale University | Schmidt M.,International Dialogue and Conflict Management | And 4 more authors.
Trends in Genetics | Year: 2013

A central undertaking in synthetic biology (SB) is the quest for the 'minimal genome'. However, 'minimal sets' of essential genes are strongly context-dependent and, in all prokaryotic genomes sequenced to date, not a single protein-coding gene is entirely conserved. Furthermore, a lack of consensus in the field as to what attributes make a gene truly essential adds another aspect of variation. Thus, a universal minimal genome remains elusive. Here, as an alternative to defining a minimal genome, we propose that the concept of gene persistence can be used to classify genes needed for robust long-term survival. Persistent genes, although not ubiquitous, are conserved in a majority of genomes, tend to be expressed at high levels, and are frequently located on the leading DNA strand. These criteria impose constraints on genome organization, and these are important considerations for engineering cells and for creating cellular life-like forms in SB. © 2012 Elsevier Ltd.

Chan C.-M.,University of Hong Kong | Danchin A.,AMAbiotics SAS | Marliere P.,Genoscope Center National Of Sequencage | Sekowska A.,AMAbiotics SAS
Environmental Microbiology | Year: 2014

Metabolism is prone to produce analogs of essential building blocks in the cell (here named paralogous metabolism). The variants result from lack of absolute accuracy in enzyme-templated reactions as well as from molecular aging. If variants were left to accumulate, the earth would be covered by chemical waste. The way bacteria cope with this situation is essentially unexplored. To gain a comprehensive understanding of Bacillus subtilis sulphur paralogous metabolism, we used expression profiling with DNA arrays to investigate the changes in gene expression in the presence of S-methyl-cysteine (SMeC) and its close analog, methionine, as sole sulphur source. Altogether, more than 200 genes whose relative strength of induction was significantly different depending on the sulphur source used were identified. This allowed us to pinpoint operon ytmItcyJKLMNytmO_ytnIJ_rbfK_ytnLM as controlling the pathway cycling SMeC directly to cysteine, without requiring sulphur oxygenation. Combining genetic and physiological experiments, we deciphered the corresponding pathway that begins with protection of the metabolite by acetylation. Oxygenation of the methyl group then follows, and after deprotection (deacetylation), N-formyl cysteine is produced. This molecule is deformylated by the second deformylase present in B.subtilisDefB, yielding cysteine. This pathway appears to be present in plant-associated microbes. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

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