No abstract

Chk1 is a member of the DNA damage response pathway, whose loss leads to replication stress and genome instability. Because of its protective role against lethal levels of DNA replication stress, Chk1 has been studied as a valuable and intriguing target for cancer therapy. However, one of the most prominent challenges with this strategy is development of resistance to Chk1 inhibitors, rendering the treatment ineffective. In their recent papers, Hunter and colleagues demonstrate multiple mechanisms by which Chk1 inhibitor resistance can arise in lymphomas. Specifically, this series of papers identify the relationship between dysfunction in NF-κB and the development of Chk1 inhibitor resistance through a loss of Chk1 activity in mouse models of lymphoma. They identify that cells lacking Chk1 activity can compensate for this loss through up-regulation of alternative pathways, such as PI3K/AKT. Finally, this work also identifies a novel role for Claspin, an important Chk1 activator, in female fertility and cancer development, furthering our understanding of how dysfunction in the Claspin/Chk1 signaling pathway affects disease states. These findings improve our understanding of drug resistance in cancer therapy, which has important implications for clinical use of Chk1 inhibitors.

Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that Ataxia telangiectasia and Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase centromeres in a DNA damage-independent manner. As ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs) in unperturbed cells, we hypothesized that ATR protects CENP-A occupancy by regulating the localization of the histone H3.3 chaperone and PML NB component, DAXX. Indeed, we found that ATR inhibition reduces DAXX association with PML NBs, resulting in the DAXX-dependent loss of CENP-A from interphase centromeres. Lastly, we demonstrate that CENP-A occupancy is not restored until G1 of the following cell cycle, leading to increased mitotic chromosome segregation defects. These findings demonstrate a novel mechanism by which ATR protects centromere identity and genome stability.