Lamin A/C promotes DNA base excision repair.

Area of Science:

• Cellular biology
• Molecular genetics
• DNA repair mechanisms

Background:

• A-type lamins (lamin A/C), encoded by the LMNA gene, are key nuclear lamina components.
• LMNA mutations cause laminopathies (e.g., Hutchinson-Gilford progeria syndrome) and are implicated in cancer.
• Lamin A/C is known to be involved in DNA double-strand break repair, but its role in base excision repair (BER) is unexplored.

Purpose of the Study:

• To investigate the role of A-type lamins in DNA base excision repair (BER).
• To elucidate the molecular mechanisms underlying lamin A/C's involvement in BER.
• To assess the consequences of lamin A/C deficiency on DNA integrity and mutation frequency.

Main Methods:

• Utilized lamin A/C-depleted cells, including Lmna null mouse embryonic fibroblasts (MEFs) and lamin A/C-knockdown U2OS cells.
• Assessed BER efficiency, activity of BER enzymes (APE1, POLβ), and poly-ADP-ribose formation.
• Quantified expression of core BER enzymes (PARP1, LIG3, POLβ) and measured 8-oxoguanine (8-oxoG) lesion accumulation.
• Induced and analyzed mutations under chronic oxidative stress conditions.

Main Results:

• Lamin A/C depletion significantly reduced BER efficiency.
• Impaired BER activity was linked to reduced APE1 and POLβ function and decreased poly-ADP-ribose chain formation.
• Lmna null MEFs showed reduced expression of PARP1, LIG3, and POLβ.
• Absence of Lmna resulted in increased 8-oxoguanine lesions and a higher frequency of GC>TA transversions, indicative of oxidative DNA damage.

Conclusions:

• Nuclear lamina integrity, supported by A-type lamins, is essential for efficient DNA base excision repair.
• Lamin A/C deficiency compromises BER pathway function, leading to oxidative DNA damage accumulation and increased mutation rates.
• These findings reveal a novel role for lamin A/C in cellular defense against DNA damage, impacting aging and cancer biology.