A focus on foci: How spatio-temporal regulation of the DNA damage response is crucial for DDR activation and cell fate

Abstract

DNA damage is a continuous threat to cells during their lifetime and it can be resolved through activation of the DNA damage response (DDR). This activation is a complicated process which involves the accumulation of a variety of DDR factors. Specific factors assemble at the site of the lesion, which is a crucial step in DDR activation. Next, the signal is amplified and more DDR factors are recruited which leads to spreading of the signal into the surrounding chromatin and transduction throughout the nucleus. This review will focus on how this spatio-temporal organization of the DDR is crucial for activation and on recent work that has showed that artificially localizing DDR factors to the chromatin induces a DDR without the need of an actual DNA lesion. This approach presents the DDR as a dynamic signaling cascade which is not only required for initiating DNA repair but can also influence cell fate. Unresolved DNA damage causes persistent signaling which leads to cell cycle arrest and can ultimately induce senescence. Because the DDR has an important role in guarding malignant transformation, this knowledge could provide more insight into how the DDR can guide premalignant lesions into senescence and thereby prevent the development of cancer.