title: Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.
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.
authors: Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors: Mayank
authors: M
authors: Singh
authors: Clayton R
authors: CR
authors: Hunt
authors: Raj K
authors: RK
authors: Pandita
authors: Rakesh
authors: R
authors: Kumar
authors: Chin-Rang
authors: CR
authors: Yang
authors: Nobuo
authors: N
authors: Horikoshi
authors: Robert
authors: R
authors: Bachoo
authors: Sara
authors: S
authors: Serag
authors: Michael D
authors: MD
authors: Story
authors: Jerry W
authors: JW
authors: Shay
authors: Simon N
authors: SN
authors: Powell
authors: Arun
authors: A
authors: Gupta
authors: Jessie
authors: J
authors: Jeffery
authors: Shruti
authors: S
authors: Pandita
authors: Benjamin P C
authors: BP
authors: Chen
authors: Dorothee
authors: D
authors: Deckbar
authors: Markus
authors: M
authors: Löbrich
authors: Qin
authors: Q
authors: Yang
authors: Kum Kum
authors: KK
authors: Khanna
authors: Howard J
authors: HJ
authors: Worman
authors: Tej K
authors: TK
authors: Pandita
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D006918:Hydroxyurea / Q000378:metabolism; D034904:Lamin Type A / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000235:genetics
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C468783:H2AX protein, human; D006657:Histones; C494847:LMNA protein, human; D034904:Lamin Type A; D006918:Hydroxyurea