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Changes in nuclear lamin-B stability marks the onset of aging in Drosophila

ABSTRACT: In this study, we showed that reduced nuclear lamin-B marks the onset of physiological decline in young adult Drosophila and its ectopic expression in dopaminergic neurons is sufficient to improve their locomotor activity during aging. Furthermore, the decline in lamin-B protein appeared to be unrelated to its mRNA level. Instead, we found drastic changes to its protein solubility during aging. Given the importance of nuclear lamin-B in genome organization and the advancement of single-cell epigenome profiling technology, our findings provide the community the basis to further study how altered level of lamin-B protein may elicit changes in gene expression that can contribute to the onset of physiological decline in animals.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE155357 | GEO | 2021/11/30

REPOSITORIES: GEO

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Age-dependent Lamin remodeling induces cardiac dysfunction via dysregulation of cardiac transcriptional programs [RNA-Seq]

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Changes in nuclear lamin-B stability marks the onset of aging in Drosophila

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Project description: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, including the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). 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. The mechanism involves impairment of the APE1 and POLβ enzyme activities in BER. Also, Lmna null mouse fibroblasts displayed reduced expression of several core BER enzymes (PARP1, LIG3, and POLβ). Moreover, the robustness of APE1 and POLβ activities and the rate of BER were enhanced by lamin A/C-augmented poly(ADP-ribose) polymer formation (PARylation). Finally, we report that HGPS fibroblasts are defective in BER. Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for human cancer and aging.

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