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Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest
Mayank Singh1, Clayton R Hunt, Raj K Pandita
1Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas, USA.
Molecular and Cellular Biology
|January 16, 2013
Summary
Lamin A/C deficiency impairs genomic stability by hindering replication fork restart after DNA damage. These cells show defects in repairing interstrand cross-links and replication stress, leading to chromosome aberrations.
Area of Science:
- Cell Biology
- Genomics
- Molecular Biology
Background:
- The LMNA gene encodes nuclear proteins lamin A and C (lamin A/C), crucial for nuclear envelope structure.
- LMNA mutations cause altered nuclear morphology, but their impact on genomic stability mechanisms remains unclear.
Purpose of the Study:
- To investigate the role of lamin A/C in maintaining genomic stability in response to DNA damaging agents and replication stress.
Main Methods:
- Assessing cellular responses to ionizing radiation, interstrand cross-link (ICL) agents (cisplatin, camptothecin, mitomycin), and replication stress (hydroxyurea).
- Analyzing DNA damage markers (γ-H2AX), DNA repair factor recruitment (FANCD2, Mre11, CtIP, Rad51, RPA), chromosome aberrations, and replication fork restart.
Main Results:
- Lamin A/C-deficient cells exhibit normal responses to ionizing radiation but are sensitive to ICL agents and replication stress.
- Deficiencies include delayed DNA repair marker removal, reduced recruitment of key repair factors, increased chromosome aberrations, and impaired replication fork restart.
Conclusions:
- Lamin A/C plays a critical role in maintaining genomic stability, particularly in facilitating replication fork restart following stalling induced by ICL damage or replication stress.
- The data suggest lamin A/C is necessary for fork regression, a process preceding DNA damage repair via homologous recombination.
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