The ATR barrier to replication-born DNA damage

Abstract

Replication comes with a price. The molecular gymnastics that occur on DNA during its duplication frequently derive to a wide spectrum of abnormalities which are still far from understood. These are brought together under the unifying term "replicative stress" (RS) which likely stands for large and unprotected regions of single-stranded DNA (ssDNA). In addition to RS, recombinogenic stretches of ssDNA are also formed at resected DNA double strand breaks (DSBs). Both situations converge on a ssDNA intermediate, which is the triggering signal for a damage situation. The cellular response in both cases is coordinated by a phosphorylation-based signaling cascade that starts with the activation of the ATR (ATM and Rad3-related) kinase. Given that ATR is essential for replicating cells, understanding the consequences of a defective ATR response for a mammalian organism has been limited until recent years. We here discuss on the topic and review the findings that connect ATR to ageing and cancer.

Figure 1. Activating ATR

The figure illustrates the steps that lead to the activation of ATR. The common signal for initiating an ATR dependent response is the presence of ssDNA. Due to the work of replicative helicases, ssDNA is most abundant during S phase, but there are other situations that can lead to ssDNA such as exposing the telomeric overhang, double-nicks generated during NER and resected DSB. ssDNA is rapidly coated by stabilizing proteins. RPA-coated ssDNA independently brings together the two components of the pathway. One one hand, RPA recruits ATRIP, which is in a complex with ATR and thus brings the kinase to the lesion. On the other hand, RPA recruits Rad17, which loads the 9-1-1. This complex is then essential to recruit and position the alosteric activator TopBP1. On close proximity, TopBP1 activates ATR.

Figure 2. ATR and cancer: Friend or Foe?

ATR can protect from cancer but, at the same time, its inhibition might be used for the killing of cells with high levels of RS. On one hand, the checkpoint response of ATR might limit the expansion of precancerous cells in which oncogenes generate RS (green). In this context, a partial reduction of ATR might allow the expansion of pretumoral cells and thus lead to cancer development (red). However, if ATR levels were very limiting (for instance, with the use of an inhibitor) this would generate lethal amounts of RS and thus lead to cell lethality (red). Importantly, such an approach would be particularly toxic for cells with high levels of RS, such as those expressing oncogenes or lacking tumor suppressors.