The Molecular Mechanism Of SLFN11 In DNA Damage Response

The genomic DNA is continuously challenged by both endogenous and exogenus DNA damage-inducing agents,which lead to many types of lesions in the DNA.To counteract the genotoxic effects of these DNA lesions,an intricate defense network known as DNA damage response has evolved.Mounting evidence demonstrates that defects in the DNA damage response pathways not only result in genomic instability,a hallmark of cancer,but also render human cancer cells more vulnerable to chemotherapy and radiation therapy.SLFN11,a nuclear protein,belongs to SLFN family that is limited to mammalian organisms.SLFN11 contains a putative RNA helicase domain at its C terminus.A previous study has shown that human SLFN11 is able to bind transfer RNA and selectively inhibit viral protein synthesis by means of codon-bias discrimination.In addition,SLFN 11 has been shown to be able to sensitize cancer cells to DNA damage-inducing agents and serve as a biomarker for DNA damage-based cancer therapy.However,how this is achieved mechanistically remains largely unclear.In this study,we show that SLFN 11 physically interacts with single-stranded DNA-binding protein replication protein A(RPA)and rapidly localizes to DNA damage sites in an RPA-dependent manner.We further demonstrate that SLFN11 is able to inhibit checkpoint maintenance and homology-directed repair through facilitating RPA removal from single-stranded DNA,thereby sensitizing cancer cells that express high endogenous levels of SLFN11 protein to DNA damage-inducing agents.Finally,we reveal that,the RPA 1-binding ability,but not the putative RNA helicase activity of SLFN11,is required for its function in the regulation of DNA damage response.Thus,SLFN11 is a novel endogenous inhibitor of DNA damage response in tumor cells that express high endogenous levels of SLFN11 protein.Taken together,our results provide novel insights into the mechanism by which SLFN11 sensitizes cancer cells that express high endogenous levels of SLFN11 protein to DNA damage-inducing agents.