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

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. WormanTej K. Panditaa

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37 Scopus citations

Abstract

To 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 γH2AX 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.

Original languageEnglish
Pages (from-to)1210-1222
Number of pages13
JournalMolecular and cellular biology
Volume33
Issue number6
DOIs
StatePublished - Mar 1 2013

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    Singh, M., Hunt, C. R., Pandita, R. K., Kumar, R., Yang, C. R., Horikoshi, N., Bachoo, R., Serag, S., Story, M. D., Shay, J. W., Powell, S. N., Gupta, A., Jeffery, J., Pandita, S., Chen, B. P. C., Deckbar, D., Löbrich, M., Yang, Q., Khanna, K. K., ... Panditaa, T. K. (2013). Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Molecular and cellular biology, 33(6), 1210-1222. https://doi.org/10.1128/MCB.01676-12