title: SLFN11 inhibits checkpoint maintenance and homologous recombination repair.
abstract: High expression levels of SLFN11 correlate with the sensitivity of human cancer cells to DNA-damaging agents. However, little is known about the underlying mechanism. Here, we show that SLFN11 interacts directly with RPA1 and is recruited to sites of DNA damage in an RPA1-dependent manner. Furthermore, we establish that SLFN11 inhibits checkpoint maintenance and homologous recombination repair by promoting the destabilization of the RPA-ssDNA complex, thereby sensitizing cancer cell lines expressing high endogenous levels of SLFN11 to DNA-damaging agents. Finally, we demonstrate that the RPA1-binding ability of SLFN11 is required for its function in the DNA damage response. Our findings not only provide novel insight into the molecular mechanisms underlying the drug sensitivity of cancer cell lines expressing SLFN11 at high levels, but also suggest that SLFN11 expression can serve as a biomarker to predict responses to DNA-damaging therapeutic agents.
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou Zhejiang, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou Zhejiang, China.
authors.forename: Jiangman
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mrinal
authors.initials: M
authors.lastname: Srivastava
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou Zhejiang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou Zhejiang, China.
authors.forename: Xin-hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou Zhejiang, China liuting518@zju.edu.cn jchen8@mdanderson.org jhuang@zju.edu.cn.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA liuting518@zju.edu.cn jchen8@mdanderson.org jhuang@zju.edu.cn.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou Zhejiang, China liuting518@zju.edu.cn jchen8@mdanderson.org jhuang@zju.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
mesh_terms: D015415:Biomarkers; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D004249:DNA Damage; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D018816:Genes, cdc; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059767:Recombinational DNA Repair; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D004277:DNA, Single-Stranded; D009687:Nuclear Proteins; C497167:RPA1 protein, human; D051716:Replication Protein A; C576668:SLFN11 protein, human
keywords: DNA damage response; RPA; checkpoint initiation; checkpoint maintenance; homologous recombination repair