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The Journal of biological chemistry v.292 no.7, 2017년, pp.2795 - 2804   SCI SCIE
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Endonuclease EEPD1 Is a Gatekeeper for Repair of Stressed Replication Forks

Kim, Hyun-Suk (From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, ) ; Nickoloff, Jac A. (the Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523, ) ; Wu, Yuehan (the Department of Medicine and the Cancer Center, University of Florida Health, Gainesville, Florida 32610, and ) ; Williamson, Elizabeth A. (the Department of Medicine and the Cancer Center, University of Florida Health, Gainesville, Florida 32610, and ) ; Sidhu, Gurjit Singh (the Department of Medicine and the Cancer Center, University of Florida Health, Gainesville, Florida 32610, and ) ; Reinert, Brian L. (the Department of Medicine and the Cancer Center, University of Florida Health, Gainesville, Florida 32610, and ) ; Jaiswal, Aruna S. (the Department of Medicine and the Cancer Center, University of Florida Health, Gainesville, Florida 32610, and ) ; Srinivasan, Gayathri (the Department of Medicine and the Cancer Center, University of Florida Health, Gainesville, Florida 32610, and ) ; Patel, Bhavita (the Department of Medicine and the Cancer Center, University o ) ; Kong, Kimi ; Burma, Sandeep ; Lee, Suk-Hee ; Hromas, Robert A. ;
  • 초록  

    Replication is not as continuous as once thought, with DNA damage frequently stalling replication forks. Aberrant repair of stressed replication forks can result in cell death or genome instability and resulting transformation to malignancy. Stressed replication forks are most commonly repaired via homologous recombination (HR), which begins with 5′ end resection, mediated by exonuclease complexes, one of which contains Exo1. However, Exo1 requires free 5′-DNA ends upon which to act, and these are not commonly present in non-reversed stalled replication forks. To generate a free 5′ end, stalled replication forks must therefore be cleaved. Although several candidate endonucleases have been implicated in cleavage of stalled replication forks to permit end resection, the identity of such an endonuclease remains elusive. Here we show that the 5′-endonuclease EEPD1 cleaves replication forks at the junction between the lagging parental strand and the unreplicated DNA parental double strands. This cleavage creates the structure that Exo1 requires for 5′ end resection and HR initiation. We observed that EEPD1 and Exo1 interact constitutively, and Exo1 repairs stalled replication forks poorly without EEPD1. Thus, EEPD1 performs a gatekeeper function for replication fork repair by mediating the fork cleavage that permits initiation of HR-mediated repair and restart of stressed forks.


  • 주제어

    DNA damage .   DNA endonuclease .   DNA repair .   DNA replication .   homologous recombination .   replication fork stress .   end resection .   nuclease.  

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