Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia

Area of Science:

• * Molecular and developmental biology
• * Cancer research
• * Genomics

Background:

• * Mutations in NF-kappaB-activating protein (NKAP) family genes are linked to human cancers.
• * The precise mechanisms by which NKAP gene mutations drive tumor initiation and progression are not fully understood.

Purpose of the Study:

• * To investigate the function of dNKAP, the Drosophila homolog of NKAP, in a Drosophila epithelial tumor model.
• * To elucidate how impaired dNKAP function contributes to genome instability and tumorigenesis.

Main Methods:

• * Characterization of dNKAP function in Drosophila wing imaginal discs.
• * Analysis of genome instability markers, including R-loop accumulation and DNA damage.
• * Investigation of signaling pathways (JNK, Notch, JAK/STAT) and their role in dNKAP-depleted tissues.
• * Transcriptome analysis to identify dysregulated pathways.
• * Genetic interaction studies with oncogenic mutations (Ras, Notch, Yki).

Main Results:

• * dNKAP knockdown in Drosophila wing imaginal discs resulted in tissue overgrowth, invasive behavior, and defects in cell polarity and adhesion.
• * Impaired dNKAP function led to R-loop accumulation and DNA damage, indicating disrupted genome integrity.
• * dNKAP depletion induced JNK-dependent apoptosis and aberrant cell proliferation, activating Notch and JAK/STAT signaling pathways.
• * Transcriptome analysis revealed misregulation of tumorigenesis-promoting and metabolic pathways.
• * dNKAP knockdown synergized with oncogenic mutations (Ras, Notch, Yki) in driving tumorigenesis.

Conclusions:

• * dNKAP functions as a tumor suppressor in Drosophila epithelia by maintaining genome stability.
• * The findings provide insights into the role of human NKAP family genes in cancer initiation and progression.