New insights into checkpoint kinase 1 in the DNA damage response signaling network

Abstract

The DNA damage response (DDR) represents a complex network of multiple signaling pathways involving cell cycle checkpoints, DNA repair, transcriptional programs, and apoptosis, through which cells maintain genomic integrity following various endogenous (metabolic) or environmental stresses. In cancer treatment, the DDR occurs in response to various genotoxic insults by diverse cytotoxic agents and radiation, representing an important mechanism limiting chemotherapeutic and radiotherapeutic efficacy. This has prompted the development of agents targeting DDR signaling pathways, particularly checkpoint kinase 1 (Chk1), which contributes to all currently defined cell cycle checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle checkpoint. Although numerous agents have been developed with the primary goal of enhancing the activity of DNA-damaging agents or radiation, the therapeutic outcome of this strategy remains to be determined. Recently, new insights into DDR signaling pathways support the notion that Chk1 represents a core component central to the entire DDR, including direct involvement in DNA repair and apoptotic events in addition to checkpoint regulation. Together, these new insights into the role of Chk1 in the DDR machinery could provide an opportunity for novel approaches to the development of Chk1 inhibitor strategies.

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Figure 1. Chk1 in DDR signaling network

DNA damage (e.g., double strand breaks/DSBs, single-strand breaks/SSBs, and stalled replication forks) generates single-strand DNA (ssDNA) that initiates ATR-mediated Chk1 activation. In this context, the ATR/ATPIP complex is recruited to ssDNA lesions via binding of ATRIP with RPA that recognizes and coats ssDNA. In conjunction with recruited/activated “sensors” and “mediators”, ATR phosphorylates Chk1 at two canonical sites (Ser345 and S317), directly leading to its activation without the homodimerization and intramolecular trans-autophosphorylation that is required for Chk2 activation. Activated Chk1 then phosphorylates diverse downstream “effectors”, which in turn are involved in cell cycle checkpoints (i.e., intra-S-, G2/M-, and G1/S-phase checkpoints), the DNA replication checkpoint, the mitotic spindle checkpoint, as well as DNA repair, apoptosis, and transcription. Consequently, Chk1 is a kinase central for the DDR signaling network, thereby representing a particularly attractive target in anti-cancer therapeutics.