Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• DNA damage is implicated in spinocerebellar neurodegenerative diseases.
• The specific DNA lesions driving these conditions remain unclear.

Purpose of the Study:

• To identify endogenous DNA lesions contributing to spinocerebellar ataxia.
• To elucidate the role of DNA damage response factors in neurodegeneration.

Main Methods:

• Analysis of pathogenic topoisomerase-1 (Top1)-DNA cleavage complexes (Top1ccs) in mouse models.
• Investigating the interplay of DNA damage response factors (ATM, tyrosyl-DNA phosphodiesterase-1, XRCC1) and Top1cc turnover.
• Inducing Top1 poisoning to observe neuropathological effects.

Main Results:

• Pathogenic Top1ccs accumulate endogenously in ataxia models.
• Defective DNA repair factors modulate Top1cc turnover independently of ATM kinase.
• Inactivating ATM and single-strand break repair factors increases Top1ccs, DNA damage, and neurodevelopmental defects.
• Direct Top1 poisoning replicates the observed neuropathology.

Conclusions:

• Top1-DNA complexes represent a critical endogenous pathogenic lesion in neurodegenerative diseases linked to DNA repair deficiency.
• Maintaining genome integrity is crucial for preventing neurological disease.