Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest

作者：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; Loebrich Markus; Yang Qin; Khanna Kum Kum; Worman Howard J; Pandita Tej K^*

来源：Molecular and Cellular Biology, 2013, 33(6): 1210-1222.

DOI：10.1128/MCB.01676-12

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 gamma-H2AX focus formation but a higher frequency of cells with delayed gamma-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 gamma-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.

• 出版日期2013-3
• 单位河北医科大学