Abstract
DNA damage occurs abundantly during normal cellular proliferation. This necessitates that cellular DNA damage response and checkpoint pathways monitor the cellular DNA damage load and that DNA damage signaling is quantitative. Yet, how DNA lesions are counted and converted into a quantitative response remains poorly understood. We have recently obtained insights into this question investigating DNA damage signaling elicited by single-stranded DNA (ssDNA). Intriguingly, our findings suggest that local and global DNA damage signaling react differentially to increasing amounts of DNA damage. In this mini-review, we will discuss these findings and put them into perspective of current knowledge on the DNA damage response.
Highlights
In order to ensure genome stability, cells need to detect DNA lesions such as DNA double-stranded breaks (DSBs) and signal their presence so that an appropriate cellular response is triggered (Zhou and Elledge 2000; Harrison and Haber 2006; Ciccia and Elledge 2010)
The central importance of the networks carrying out this fundamental task is underscored by the observation that mutations in DNA damage signaling proteins often coincide with a predisposition for cancer development and progeria (O’Driscoll 2012)
DNA damage signaling is mediated by proteins of the DNA damage checkpoint, which can recognize DNA structures that indicate the presence of DNA lesions and convert them into downstream DNA damage signals
Summary
In order to ensure genome stability, cells need to detect DNA lesions such as DNA double-stranded breaks (DSBs) and signal their presence so that an appropriate cellular response is triggered (Zhou and Elledge 2000; Harrison and Haber 2006; Ciccia and Elledge 2010). All three scenarios—a high number of DNA lesions, the presence of persistent lesions and the occurence of DNA lesions or stalled/ broken replication forks in S phase—can be seen as severe threat to cellular survival calling for a cell-wide response and activation of the DNA damage checkpoint.
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