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Identifizierung genetischer Determinanten der Mikrokernbildung

von NFI Redaktion

In a study recently published in Nature, researchers identified the genetic determinants of micronucleus formation (MN).

Study: Identification of genetic determinants of micronucleus formation in vivo. Image source: Dimarion/Shutterstock.com








Study: Genetic Determinants of Micronucleus Formation In Vivo. Image source: Dimarion/Shutterstock.com

Background

Genomic instability and extracellular MN accumulation are hallmarks of various diseases, including inflammatory conditions, cancer, and aging. MN are chromosome fragments that arise from errors in mitotic segregation or unrepaired DNA breaks.

MN are protected by an atypical nuclear envelope and can persist across multiple cell generations, acquire aberrant epigenetic markings, and replicate their DNA.

Furthermore, the nuclear envelope of MN can rupture, leading to the accumulation of MN DNA damage, chromosomal recombination, and a strong proinflammatory response that can drive cellular senescence.

The Study and Results

The study investigated the factors regulating MN formation in vivo, examining over 6,000 mice in 997 mutant lines with loss of function and using a method to count MN in erythrocytes.

This defined genes where disruption decreased (-MN) or increased (+MN) MN formation and accumulation compared to wild-type controls (WT). Hits were categorized based on statistical significance into three tiers (1–3).

Subsequently, the team selected seven -MN genes from Tier 1 and disrupted them using clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) editing in human CHP-212 cells.

The cells were exposed to a low, chronic hydroxyurea dose, increasing the average basal rate of MN in WT cells from 1.5% to 5%.

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