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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 (US)
Pages (from-to)1210-1222
Number of pages13
JournalMolecular and Cellular Biology
Volume33
Issue number6
DOIs
StatePublished - Mar 2013

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Lamin Type A
DNA Damage
Genomic Instability
Chromosome Aberrations
DNA Repair
Camptothecin
Hydroxyurea
Homologous Recombination
Essential Genes
Nuclear Envelope
Mitomycin
Nuclear Proteins
Protein C
Ionizing Radiation
Cisplatin
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Singh, M., Hunt, C. R., Pandita, R. K., Kumar, R., Yang, C. R., Horikoshi, N., ... 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

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

In: Molecular and Cellular Biology, Vol. 33, No. 6, 03.2013, p. 1210-1222.

Research output: Contribution to journalArticle

Singh, M, Hunt, CR, Pandita, RK, Kumar, R, Yang, CR, Horikoshi, N, Bachoo, R, Serag, S, Story, MD, Shay, JW, Powell, SN, Gupta, A, Jeffery, J, Pandita, S, Chen, BPC, Deckbar, D, Löbrich, M, Yang, Q, Khanna, KK, Worman, HJ & Panditaa, TK 2013, 'Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest', Molecular and Cellular Biology, vol. 33, no. 6, pp. 1210-1222. https://doi.org/10.1128/MCB.01676-12
Singh M, Hunt CR, Pandita RK, Kumar R, Yang CR, Horikoshi N et al. Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Molecular and Cellular Biology. 2013 Mar;33(6):1210-1222. https://doi.org/10.1128/MCB.01676-12
Singh, Mayank ; Hunt, Clayton R. ; Pandita, Raj K. ; Kumar, Rakesh ; Yang, Chin Rang ; Horikoshi, Nobuo ; Bachoo, Robert ; Serag, Sara ; Story, Michael D. ; Shay, Jerry W. ; Powell, Simon N. ; Gupta, Arun ; Jeffery, Jessie ; Pandita, Shruti ; Chen, Benjamin P C ; Deckbar, Dorothee ; Löbrich, Markus ; Yang, Qin ; Khanna, Kum Kum ; Worman, Howard J. ; Panditaa, Tej K. / Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. In: Molecular and Cellular Biology. 2013 ; Vol. 33, No. 6. pp. 1210-1222.
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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.",
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AU - Hunt, Clayton R.

AU - Pandita, Raj K.

AU - Kumar, Rakesh

AU - Yang, Chin Rang

AU - Horikoshi, Nobuo

AU - Bachoo, Robert

AU - Serag, Sara

AU - Story, Michael D.

AU - Shay, Jerry W.

AU - Powell, Simon N.

AU - Gupta, Arun

AU - Jeffery, Jessie

AU - Pandita, Shruti

AU - Chen, Benjamin P C

AU - Deckbar, Dorothee

AU - Löbrich, Markus

AU - Yang, Qin

AU - Khanna, Kum Kum

AU - Worman, Howard J.

AU - Panditaa, Tej K.

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N2 - 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.

AB - 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.

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