Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase.

摘要: The ATR-Chk1 pathway is critical for DNA damage responses and cell-cycle progression. Chk1 inhibition more deleterious to cycling cells than ATR inhibition, raising questions about functions in the absence of extrinsic replication stress. Here we show that a key role S phase coordinate RRM2 accumulation origin firing. inhibitor (ATRi) induces massive ssDNA catastrophe fraction early S-phase cells. In other cells, however, ATRi moderate triggers DNA-PK Chk1-mediated backup suppress creates threshold such selectively kills under high stress, whereas cell death at lower threshold. levels ATRi-induced correlate with sensitivity panel lines, suggesting could be predictive cancer