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ATM-Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response
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نویسنده
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martin n.t. ,nakamura k. ,davies r. ,nahas s.a. ,brown c. ,tunuguntla r. ,gatti r.a. ,hu h.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 5
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چکیده
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Atm plays a critical role in cellular responses to dna double-strand breaks (dsbs). we describe a new atm-mediated dsb-induced dna damage response pathway involving microrna (mirna): irradiation (ir)-induced dsbs activate atm,which leads to the downregulation of mir-335,a mirna that targets ctip,which is an important trigger of dna end resection in homologous recombination repair (hrr). we demonstrate that creb is responsible for a large portion of mir-335 expression by binding to the promoter region of mir-335. creb binding is greatly reduced after ir,corroborating with previous studies that ir-activated atm phosphorylates creb to reduce its transcription activity. overexpression of mir-335 in hela cells resulted in reduced ctip levels and post-ir colony survival and brca1 foci formation. further,in two patient-derived lymphoblastoid cell lines with decreased post-ir colony survival,a radiosensitive phenotype,we demonstrated elevated mir-335 expression,reduced ctip levels,and reduced brca1 foci formation. colony survival,brca1 foci,and ctip levels were partially rescued by mirna antisense amo-mir-335 treatment. taken together,these findings strongly suggest that an atm-dependent creb-mir-335-ctip axis influences the selection of hrr for repair of certain dsb lesions. © 2013 martin et al.
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آدرس
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department of pathology and laboratory medicine,university of california los angeles,los angeles,ca,united states,ucla biomedical physics interdepartmental graduate program,university of california los angeles,los angeles,ca, United States, department of pathology and laboratory medicine,university of california los angeles,los angeles,ca, United States, department of pathology and laboratory medicine,university of california los angeles,los angeles,ca, United States, department of pathology and laboratory medicine,university of california los angeles,los angeles,ca, United States, department of pathology and laboratory medicine,university of california los angeles,los angeles,ca, United States, department of pathology and laboratory medicine,university of california los angeles,los angeles,ca, United States, department of pathology and laboratory medicine,university of california los angeles,los angeles,ca,united states,ucla biomedical physics interdepartmental graduate program,university of california los angeles,los angeles,ca,united states,jonsson comprehensive cancer center,university of california los angeles,los angeles,ca,united states,department of human genetics,david geffen school of medicine,university of california los angeles,los angeles,ca, United States, department of pathology and laboratory medicine,university of california los angeles,los angeles,ca,united states,jonsson comprehensive cancer center,university of california los angeles,los angeles,ca, United States
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Authors
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