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Nucleic Acids Research Advance Access published online on October 2, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn636
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genomics

Evolutionary origins of human apoptosis and genome-stability gene networks

Mauro A. A. Castro1,2,*, Rodrigo J. S. Dalmolin1, José C. F. Moreira1, José C. M. Mombach3 and Rita M. C. de Almeida4

1Bioinformatics Unit, Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos 2600-anexo, Porto Alegre 90035-003, 2Department of Biological Sciences, Lutheran University of Brazil, Gravataí 94170-240, 3Department of Physics, Federal University of Santa Maria (UFSM), Santa Maria 97105-900 and 4Institute of Physics, Federal University of Rio Grande do Sul (UFRGS), Avenida Bento Gonçalves 9500, Porto Alegre 91501-970, Caixa Postal 15051, Brazil

*To whom correspondence should be addressed. Tel: +55 51 3308 5577; Fax: +55 51 3308 5540; Email: mauro{at}ufrgs.br

Correspondence may also be addressed to Rita M.C. de Almeida. Tel: +55 51 3308 6521; Fax: +55 51 3308 7286; Email: rita{at}if.ufrgs.br

Received May 23, 2008. Revised September 14, 2008. Accepted September 15, 2008.

Apoptosis is essential for complex multicellular organisms and its failure is associated with genome instability and cancer. Interactions between apoptosis and genome-maintenance mechanisms have been extensively documented and include transactivation-independent and -dependent functions, in which the tumor-suppressor protein p53 works as a ‘molecular node’ in the DNA-damage response. Although apoptosis and genome stability have been identified as ancient pathways in eukaryote phylogeny, the biological evolution underlying the emergence of an integrated system remains largely unknown. Here, using computational methods, we reconstruct the evolutionary scenario that linked apoptosis with genome stability pathways in a functional human gene/protein association network. We found that the entanglement of DNA repair, chromosome stability and apoptosis gene networks appears with the caspase gene family and the antiapoptotic gene BCL2. Also, several critical nodes that entangle apoptosis and genome stability are cancer genes (e.g. ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6 and TP53), although their orthologs have arisen in different points of evolution. Our results demonstrate how genome stability and apoptosis were co-opted during evolution recruiting genes that merge both systems. We also provide several examples to exploit this evolutionary platform, where we have judiciously extended information on gene essentiality inferred from model organisms to human.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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M. A. A. Castro, J. L. R. Filho, R. J. S. Dalmolin, M. Sinigaglia, J. C. F. Moreira, J. C. M. Mombach, and R. M. C. de Almeida
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