[SLFN11 inhibition rescues the Fanconi anemia phenotype by stabilizing stalled replication forks].

Abstract

Fanconi anemia (FA) is a rare hereditary disorder characterized by hypersensitivity to the interstrand crosslinks (ICLs) induced by cisplatin, mitomycin C, or formaldehyde. We found that inhibition of SLFN11, which has been identified as a dominant determinant of responses to various antitumor drugs such as cisplatin, camptothecin, and PARP inhibitors, rescued ICL sensitivity and partially alleviated FA phenotype by stabilizing replication forks. This suggests that SLFN11 intensifies DNA damage sensitivity in FA cells, and could be a novel therapeutic target for the FA phenotype. We also found that human SLFN11 and mouse Slfn8/9 share a functional similarity. In this review, we summarize the interplay between SLFN11 and DNA damage, including functional analysis of SLFN11 and its mouse ortholog.