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Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.

Singh, Mayank and Hunt, Clayton R. and Pandita, Raj K. and Kumar, Rakesh and Yang, Chin-Rang and Horikoshi, Nobuo and Bachoo, Robert and Serag, Sara and Story, Michael D. and Shay, Jerry W. and Powell, Simon N. and Gupta, Arun and Jeffery, Jessie and Pandita, Shruti and Chen, Benjamin P. C. and Deckbar, Dorothee and Löbrich, Markus and Yang, Qin and Khanna, Kum Kum and Worman, Howard J. and Pandita, Tej K. (2013):
Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.
In: Molecular and cellular biology, pp. 1210-22, 33, (6), ISSN 1098-5549, [Article]

Abstract

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.

Item Type: Article
Erschienen: 2013
Creators: Singh, Mayank and Hunt, Clayton R. and Pandita, Raj K. and Kumar, Rakesh and Yang, Chin-Rang and Horikoshi, Nobuo and Bachoo, Robert and Serag, Sara and Story, Michael D. and Shay, Jerry W. and Powell, Simon N. and Gupta, Arun and Jeffery, Jessie and Pandita, Shruti and Chen, Benjamin P. C. and Deckbar, Dorothee and Löbrich, Markus and Yang, Qin and Khanna, Kum Kum and Worman, Howard J. and Pandita, Tej K.
Title: Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.
Language: English
Abstract:

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.

Journal or Publication Title: Molecular and cellular biology
Volume: 33
Number: 6
Divisions: 10 Department of Biology
10 Department of Biology > Radiation Biology and DNA Repair
Date Deposited: 13 May 2013 06:41
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