A schematic model of our results. In wild-type (WT) cells (A), the progression of the DNA replication forks is often hindered because of replication stress such as those caused by R-loops or formaldehyde damage. These are proposed endogenous sources of replication stress/DNA damage relevant to FA. The stalled forks undergo remodeling termed “fork reversal,” resulting in the 4-way structure. The reversed fork is digested by nucleases DNA2 or MRE11, leading to genome instability, but the degradation is prevented by FA proteins, including RAD51, FANCD2, and others. We propose SLFN11 is acting against fork protection by RAD51. In FA cells such as FANCD2^−/− background (B), SLFN11 expression results in excess fork degradation and inefficient ICL repair, which causes the indicated FA phenotypes. The deletion of SLFN11 (C) places more RAD51 on the nascent DNA, enabling efficient fork protection and reversal of the FA phenotype.