Document Detail


Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.
MedLine Citation:
PMID:  23319047     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 impacts 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 interstrand cross-links (ICLs) or replication stress. In response to treatment with ICL agents (cisplatin, camptothecin, and mitomycin), lamin A/C-deficient cells displayed normal γ-H2AX focus 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 can be interpreted to 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.
Authors:
Mayank Singh; Clayton R Hunt; Raj K Pandita; Rakesh Kumar; Chin-Rang Yang; Nobuo Horikoshi; Robert Bachoo; Sara Serag; 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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-01-14
Journal Detail:
Title:  Molecular and cellular biology     Volume:  33     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-22     Completed Date:  2013-07-05     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1210-22     Citation Subset:  IM    
Affiliation:
Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Cell Line, Tumor
Chromosome Aberrations
DNA Damage*
DNA Repair / genetics
DNA Replication*
Fanconi Anemia Complementation Group D2 Protein / genetics,  metabolism
Fibroblasts / metabolism
Gene Expression / genetics
HEK293 Cells
Histones / genetics,  metabolism
Homologous Recombination / genetics
Humans
Hydroxyurea / metabolism
Lamin Type A / deficiency*,  genetics*,  metabolism
MCF-7 Cells
Mice
Radiation, Ionizing
Signal Transduction / genetics
Grant Support
ID/Acronym/Agency:
1P30 CA142543/CA/NCI NIH HHS; P30 CA142543/CA/NCI NIH HHS; R01 CA154320/CA/NCI NIH HHS; R01CA129537/CA/NCI NIH HHS; R01CA154320/CA/NCI NIH HHS; R13CA130756/CA/NCI NIH HHS; U19A1091175//PHS HHS
Chemical
Reg. No./Substance:
0/FANCD2 protein, human; 0/Fanconi Anemia Complementation Group D2 Protein; 0/H2AFX protein, human; 0/Histones; 0/LMNA protein, human; 0/Lamin Type A; 127-07-1/Hydroxyurea
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