Lamin A/C promotes DNA base excision repair

Abstract

The A-type lamins (lamin A/C), encoded by the LMNA gene, are important structural components of the nuclear lamina. LMNA mutations lead to degenerative disorders known as laminopathies, including the premature aging disease Hutchinson-Gilford progeria syndrome. In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells (Lmna null MEFs and lamin A/C-knockdown U2OS). The mechanism involves impairment of the APE1 and POLβ BER activities, partly effectuated by associated reduction in poly-ADP-ribose chain formation. Also, Lmna null MEFs displayed reduced expression of several core BER enzymes (PARP1, LIG3 and POLβ). Absence of Lmna led to accumulation of 8-oxoguanine (8-oxoG) lesions, and to an increased frequency of substitution mutations induced by chronic oxidative stress including GC>TA transversions (a fingerprint of 8-oxoG:A mismatches). Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for cancer and aging.

Dissecting the Effect of a 3D Microscaffold on the Transcriptome of Neural Stem Cells with Computational Approaches: A Focus on Mechanotransduction

“…Lastly, we show that the mechanically induced effect on cell biology also implicates the nucleus, as mechanotransduction can modulate the shape and the structure of the nucleus in response to changes in the interaction between cytoskeleton and nucleoskeleton [74]. We found multiple nuclear processes involved (DNA repair mechanisms, modulation of transcription, regulation of molecule transport through nuclear membrane, RNA metabolism, and activation of specific mechanosensitive gene), all already linked to mechanotransduction processes [78][79][80][81][82][83][84][85][86][87]. We assessed the differences in cytoskeleton organization and adhesion complexes formation evaluating the specific deregulation in genes' pertaining to these processes, along with a morphological analysis with immunofluorescence and ESEM technology.…”

“…Together, these pathways point out alterations in DNA repair mechanisms, both involving double-or single-strand break, in response to the Nichoid-growth. Components of the nucleoskeleton, which is prone to mechanical stimuli, have been related to homologous recombination and DNA base excision repair [78,79].…”

Addressing the Molecular Mechanism of Longitudinal Lamin Assembly Using Chimeric Fusions

“…By doing this, lamins provide mechanical stability, which is the core function of IF family. Moreover, lamins are involved in a broad variety of cellular processes including chromatin organization and transcription, DNA replication and repair, cell differentiation, mitosis and gene expression [2][3][4][5][6][7]. As a result, mutations in the lamin genes cause a wide range of diseases called laminopathies, including Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria syndrome [8].…”

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

“…[50][51][52] Lamin-B1 participates in the regulation of NER 53 and lamin-A/C promotes base excision repair. 54 On the other hand, loss of NPCs results deficient nuclear import and export in mNE. As a consequence, the recruitments of DNA repair factors (eg, 53BP1, Rad51, Rad50, Rad17, BRCA1, MRE11, NBS1, XPC and XPA) and DDR players (eg, ATM and p53) into these micronuclei are significantly blocked, 24,42,43,[55][56][57][58] resulting extensive defects in DNA damage sensing and repair.…”