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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. ; Pandita, Tej K. (2013)
Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.
In: Molecular and cellular biology, 33 (6)
Artikel, Bibliographie

Kurzbeschreibung (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.

Typ des Eintrags: Artikel
Erschienen: 2013
Autor(en): 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. ; Pandita, Tej K.
Art des Eintrags: Bibliographie
Titel: Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.
Sprache: Englisch
Publikationsjahr: März 2013
Titel der Zeitschrift, Zeitung oder Schriftenreihe: Molecular and cellular biology
Jahrgang/Volume einer Zeitschrift: 33
(Heft-)Nummer: 6
Kurzbeschreibung (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.

Fachbereich(e)/-gebiet(e): 10 Fachbereich Biologie
10 Fachbereich Biologie > Radiation Biology and DNA Repair
Hinterlegungsdatum: 13 Mai 2013 06:41
Letzte Änderung: 13 Mai 2013 06:41
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