| Lamin A/C Depletion Enhances DNA Damage Induced Stalled Replication Fork Arrest. | |
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MedLine Citation:
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PMID: 23319047 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in LMNA result in altered nuclear morphology, but how this imparts the mechanisms that maintain genomic stability is unclear. Here we report that lamin A/C-deficient cells have a normal response to ionizing radiation but are sensitive to agents that cause inter-strand cross links (ICLs) or replication stress. In response to treatment with ICL agents (cis-platin, campthotecin, mitomycin), lamin A/C-deficient cells displayed normal γ-H2AX foci formation but a higher frequency of cells with delayed γ-H2AX removal, decreased recruitment of the FANCD2 repair factor and a higher frequency of chromosome aberrations. Similarly, following hydroxyurea induced replication stress, lamin A/C deficient cells had an increased frequency of cells with delayed disappearance of γ-H2AX foci and defective repair factor recruitment (Mre11, CtIP, Rad51, RPA and FANCD2). Replicative stress also resulted in a higher frequency of chromosomal aberrations as well as defective replication restart. Taken together, the data suggest that lamin A/C has a role in the restart of stalled replication forks, a prerequisite for initiation of DNA damage repair by the homologous recombination pathway, which is intact in lamin A/C-deficient cells. We propose that lamin A/C is required for maintaining genomic stability following replication fork stalling, induced by either ICL damage or replicative stress, in order to facilitate fork regression prior to DNA damage repair. |
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Authors:
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Mayank Singh; Clayton R Hunt; Raj K Pandita; Rakesh Kumar; Chin-Rang Yang; Nobuo Horikoshi; Robert Bachoo; Sara Sarag; Michael D Story; Jerry W Shay; Simon N Powell; Arun Gupta; Jessie Jeffery; Shruti Pandita; Benjamin P C Chen; Dorothee Deckbar; Markus Löbrich; Qin Yang; Kum Kum Khanna; Howard J Worman; Tej K Pandita |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-14 |
Journal Detail:
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Title: Molecular and cellular biology Volume: - ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Radiation Oncology. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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