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The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
2011 (English)In: Molecular Oncology, ISSN 1574-7891, Vol. 5, no 4, 387-393 p.Article, review/survey (Refereed) Published
Abstract [en]

Poly (ADP-ribose) polymerase (PARP) inhibitors effectively kill tumours defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. It is suggested that PARP inhibitors cause an increase in DNA single-strand breaks (SSBs), which are converted during replication to irreparable toxic DNA double-strand breaks (DSBs) in BRCA1/2 defective cells. There are a number of recent reports challenging this model. Here, alternative models that are not mutually exclusive are presented to explain the synthetic lethality between BRCA1/2 and PARP inhibitors. One such model proposes that PARP inhibition causes PARP-1 to be trapped onto DNA repair intermediates, especially during base excision repair. This may in turn cause obstruction to replication forks, which require BRCA-dependent homologous recombination to be resolved. In another model, PARP is directly involved in catalysing replication repair in a distinct pathway from homologous recombination. Experimental evidence supporting these novel models to explain the PARP-BRCA synthetic lethality are discussed. (C) 2011 Federation of European Biochemical Societies.

Place, publisher, year, edition, pages
2011. Vol. 5, no 4, 387-393 p.
Keyword [en]
Review, Homologous recombination, Stalled replication fork, DNA double-strand breaks, Poly(ADP-ribose) polymerase, BRCA1, BRCA2, Synthetic lethality, Cancer
National Category
Natural Sciences
URN: urn:nbn:se:su:diva-68278DOI: 10.1016/j.molonc.2011.07.001ISI: 000295311700009OAI: diva2:477990
authorCount :1Available from: 2012-01-15 Created: 2012-01-03 Last updated: 2012-01-15Bibliographically approved

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Helleday, Thomas
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