The p53-p21WAF1 checkpoint pathway plays a protective role in preventing DNA rereplication induced by abrogation of FOXF1 function

► FOXF1 knockdown renders p53-null and p21-null cells susceptible to DNA rereplication. ► FOXF1 knockdown activates the ATM/ATR-p53-p21 DNA damage checkpoint pathways. ► Activation of the p53-p21 pathway by FOXF1 knockdown inhibits the CDK2-Rb cascade. ► Inhibition of CDK2 by elevated p21 induces G1 arrest to prevent DNA rereplication. ► FOXF1 is silenced in breast and colorectal cancer cell lines with inactive p53.