Fanconi anemia proteins stabilize replication forks |
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| Authors: | Wang Lily Chien Stone Stacie Hoatlin Maureen Elizabeth Gautier Jean |
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| Institution: | aInstitute for Cancer Genetics, Columbia University, New York, NY 10032, USA;bIntegrated Program in Cellular, Molecular, Structural and Genetic Studies, Columbia University, New York, NY 10032, USA;cDivision of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, USA;dDepartment of Genetics and Development, Columbia University, New York, NY 10032, USA |
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| Abstract: | Fanconi anemia (FA) is a recessive genetic disorder characterized by hypersensitivity to crosslinking agents that has been attributed to defects in DNA repair and/or replication. FANCD2 and the FA core complex bind to chromatin during DNA replication; however, the role of FA proteins during replication is unknown. Using Xenopus cell-free extracts, we show that FANCL depletion results in defective DNA replication restart following treatment with camptothecin, a drug that results in DSBs during DNA replication. This defect is more pronounced following treatment with mitomycin C, presumably because of an additional role of the FA pathway in DNA crosslink repair. Moreover, we show that chromatin binding of FA core complex proteins during DNA replication follows origin assembly and origin firing and is dependent on the binding of RPA to ssDNA while FANCD2 additionally requires ATR, consistent with FA proteins acting at replication forks. Together, our data suggest that FA proteins play a role in replication restart at collapsed replication forks. |
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| Keywords: | Fanconi anemia Mitomycin C Replication forks Replication restart |
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