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EEPD1 Rescues Stressed Replication Forks and Maintains Genome Stability by Promoting End Resection and Homologous Recombination Repair
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نویسنده
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wu y. ,lee s.-h. ,williamson e.a. ,reinert b.l. ,cho j.h. ,xia f. ,jaiswal a.s. ,srinivasan g. ,patel b. ,brantley a. ,zhou d. ,shao l. ,pathak r. ,hauer-jensen m. ,singh s. ,kong k. ,wu x. ,kim h.-s. ,beissbarth t. ,gaedcke j. ,burma s. ,nickoloff j.a. ,hromas r.a.
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منبع
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plos genetics - 2015 - دوره : 11 - شماره : 12
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چکیده
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Replication fork stalling and collapse is a major source of genome instability leading to neoplastic transformation or cell death. such stressed replication forks can be conservatively repaired and restarted using homologous recombination (hr) or non-conservatively repaired using micro-homology mediated end joining (mmej). hr repair of stressed forks is initiated by 5’ end resection near the fork junction,which permits 3’ single strand invasion of a homologous template for fork restart. this 5’ end resection also prevents classical non-homologous end-joining (cnhej),a competing pathway for dna double-strand break (dsb) repair. unopposed nhej can cause genome instability during replication stress by abnormally fusing free double strand ends that occur as unstable replication fork repair intermediates. we show here that the previously uncharacterized exonuclease/endonuclease/phosphatase domain-1 (eepd1) protein is required for initiating repair and restart of stalled forks. eepd1 is recruited to stalled forks,enhances 5’ dna end resection,and promotes restart of stalled forks. interestingly,eepd1 directs dsb repair away from cnhej,and also away from mmej,which requires limited end resection for initiation. eepd1 is also required for proper atr and chk1 phosphorylation,and formation of gamma-h2ax,rad51 and phospho-rpa32 foci. consistent with a direct role in stalled replication fork cleavage,eepd1 is a 5’ overhang nuclease in an obligate complex with the end resection nuclease exo1 and blm. eepd1 depletion causes nuclear and cytogenetic defects,which are made worse by replication stress. depleting 53bp1,which slows cnhej,fully rescues the nuclear and cytogenetic abnormalities seen with eepd1 depletion. these data demonstrate that genome stability during replication stress is maintained by eepd1,which initiates hr and inhibits cnhej and mmej. © 2015 wu et al.
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آدرس
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department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of biochemistry and molecular biology,indiana university school of medicine,indianapolis,in, United States, department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of radiation oncology,comprehensive cancer center,the ohio state university,columbus,oh, United States, department of radiation oncology,comprehensive cancer center,the ohio state university,columbus,oh, United States, department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of pharmaceutical sciences,university of arkansas for medical sciences,little rock,ar, United States, department of pharmaceutical sciences,university of arkansas for medical sciences,little rock,ar, United States, department of pharmaceutical sciences,university of arkansas for medical sciences,little rock,ar, United States, department of pharmaceutical sciences,university of arkansas for medical sciences,little rock,ar, United States, department of medicine and the cancer center,university of florida health,gainesville,fl,united states,department of medicine,university of new mexico health science center,and the albuquerque veteran’s administration hospital,albuquerque,nm, United States, department of craniofacial regeneration,college of dental medicine,columbia university,new york,ny,united states,department of medicine and the cancer center,university of florida health,gainesville,fl, United States, department of molecular and experimental medicine,scripps research institute,la jolla,ca, United States, department of biochemistry and molecular biology,indiana university school of medicine,indianapolis,in, United States, department of medical statistics,and general,visceral,and pediatric surgery,university medical center göttingen,göttingen, Germany, department of medical statistics,and general,visceral,and pediatric surgery,university medical center göttingen,göttingen, Germany, department of radiation oncology,university of texas southwestern,dallas,tx, United States, department of environmental and radiological health sciences,colorado state university,fort collins,co, United States, department of medicine and the cancer center,university of florida health,gainesville,fl, United States
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Authors
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