Abstract
Homologous recombination (HR) is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB). However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The cellular factors that restrict HR processes in mammalian cells are only beginning to be elucidated. The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardian of the genome, would impair an error-free repair process. Here, we show for the first time that p53 downregulates foci formation of the RAD51 recombinase in response to replicative stress in H1299 lung cancer cells in a manner that is independent of its role as a transcription factor. We find that this downregulation of HR is not only completely dependent on the binding site of p53 with replication protein A but also the ATR/ATM serine 15 phosphorylation site. Genetic analysis suggests that ATR but not ATM kinase modulates p53's function in HR. The suppression of HR by p53 can be bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53's role as a guardian of the genome. As a result, transactivation-inactive p53 does not compromise the resistance of H1299 cells to the interstrand crosslinking agent mitomycin C. Altogether, our data support a model in which p53 plays an anti-recombinogenic role in the ATR-dependent mammalian replication checkpoint but does not impair a cell's ability to use HR for the removal of DSB induced by cytotoxic agents.
Highlights
Genetic exchanges mediated by homologous DNA sequences must be tightly regulated to maintain genomic stability [1]
DNA double-strand breaks (DSB) occurring in S-phase post-replication or in G2 are repaired by homologous recombination (HR) in a typically errorfree manner because homologous DNA sequence on the sister chromatid can serve as an accurate template for repair
Because careful control of HR activities is important for the response to stalled or collapsed replication forks, elucidating the role of p53 in HR is critical for a better understanding of tumor initiation and progression
Summary
Genetic exchanges mediated by homologous DNA sequences must be tightly regulated to maintain genomic stability [1]. An active homologous recombination (HR) pathway is needed for the repair and restart of collapsed DNA replication forks [2]. Cells with defects in HR are impaired in their ability to remove DNA interstrand crosslinks (ICL) as produced for example by mitomycin C (MMC). DNA double-strand breaks (DSB) occurring in S-phase post-replication or in G2 are repaired by HR in a typically errorfree manner because homologous DNA sequence on the sister chromatid can serve as an accurate template for repair. Spontaneous DNA exchanges between homologous sequences in mitotically growing cells have to be limited and HR activities at stalled replication forks may not always be desirable [1,3,4]. The anti-recombinogenic factors that restrict HR in mammalian cells are only beginning to be elucidated
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