In response to UV damage or replication fork stalling (left side), the presence of single-stranded DNA triggers binding by RPA, which independently recruits the ATR-ATRIP complex and the RAD17 complex. Subsequently, the 9-1-1 complex, composed of RAD9, RAD1, and HUS1, and TOPB1 are recruited, which in turn activates ATR. There are hundreds of downstream targets of the ATR kinase, including CHK1, BRCA1, and H2AX. This signaling cascade elicits a host of cellular responses, including DNA repair and cell cycle arrest. Improper resolution of DNA damage can trigger cell death or cellular senescence. Double-strand breaks (right side) trigger the recruitment of the MRN complex, composed of MRE11, RAD50, and NBS1, which binds and activates ATM. Similar to ATR, ATM phosphorylates a host of downstream effectors to trigger DNA damage response pathways. Studies from Stephen Elledge’s laboratory were instrumental in the understanding of how DNA damage is sensed and then leads to activation of downstream signaling cascades that trigger the DNA damage response.