Powerful human DNA mutators identified

Scientists from the Institut Pasteur, the French National Center for Scientific Research (CNRS), and the French National Institute for Health and Medical Research (Inserm) have shown that a cellular protein, APOBEC3A, known for its antiviral activity, is also capable of mutagenic activity on human cell DNA. This discovery suggests that this protein plays a role in the cellular DNA degradation occurring in apoptosis, programmed cell death, and cancer genesis. This work has been published on the PNAS website.

Scientists from the Institut Pasteur and the CNRS, making up the Molecular Retrovirology Unit, along with Inserm colleagues, have identified a new function of APOBEC3A, a protein responsible for blocking viral replication in the case of infection. The teams have shown that this protein can induce mutations in its own DNA.

APOBEC3 cellular proteins are known for their antiviral activity. These proteins block the replication of viruses by generating numerous mutations thus "machine-gunning" the viral genome. This is most notably the action taken against AIDS, hepatitis B, and papillomaviruses.

Scientists have shown that under certain cellular conditions APOBEC3A directs its mutagenic activity against its own nuclear and mitochondrial DNA. Given that mitochondrial DNA is directly involved in apoptosis, or programmed cell death, this new identification of APOBEC3A activity suggests that it is part of the phenomenon.

Additionally, in-depth analyses have already shown that the most frequently observed mutations in cancerous cells carry the same signature as those seen with APOBEC3A in nuclear DNA. This indicates the possible involvement of this protein in mechanisms linked to cancer genesis.

This work could open new therapeutic avenues towards the development of molecules capable of blocking this powerful human DNA mutator.

Image : Overall structure of APOBEC 3 © Institut Pasteur

Source

Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism, PNAS en ligne.

Rodolphe Suspène ^a,1, Marie-Ming Aynaud ^a,1, Denise Guétard ^a, Michel Henry ^a, Grace Eckhoff ^a, Agnès Marchio ^b, Pascal Pineau ^b, Anne Dejean ^b, Jean-Pierre Vartanian ^a, and Simon Wain-Hobson ^a

(a) Institut Pasteur, unité de Rétrovirologie moléculaire, Centre national de recherche scientifique URA 3015, 75724 Paris cedex 15, France

(b) Institut Pasteur, unité de recherche Organisation nucléaire et oncogenèse, Institut national de la santé et de la recherche médicale U993, 75724 Paris cedex 15, France

1 Both authors have contributed equally to this study.

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