The deoxyribose phosphate lyase of DNA polymerase β suppresses a processive DNA synthesis to prevent trinucleotide...

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Trinucleotide repeat (TNR) instability is implicated in over 42 neurodegenerative diseases and cancers.
• The precise molecular mechanisms driving TNR instability are not fully understood.
• The DNA base excision repair (BER) pathway, particularly DNA polymerase β (pol β), is known to regulate somatic TNR instability.

Purpose of the Study:

• To investigate the specific role of the pol β dRP lyase domain in preventing somatic TNR instability.
• To elucidate the molecular mechanism by which pol β dRP lyase activity impacts TNR stability.

Main Methods:

• Investigating the effects of pol β dRP lyase deficiency on TNR instability in cellular models.
• Analyzing the interaction between pol β and its DNA template in the presence and absence of functional dRP lyase activity.
• Assessing the impact of wild-type pol β complementation on TNR instability in deficient cells.

Main Results:

• Deficiency in pol β dRP lyase activity leads to 'tethering' of pol β to the DNA template, promoting processive DNA synthesis.
• This processive synthesis results in DNA strand slippage and trinucleotide repeat deletion.
• Complementation with wild-type pol β protein restored normal TNR stability, eliminating deletions.

Conclusions:

• Pol β dRP lyase activity is crucial for restraining pol β-template interactions, thereby suppressing processive DNA synthesis and preventing TNR deletion.
• The findings suggest that pol β dRP lyase inhibition could be a potential therapeutic strategy for TNR-expansion diseases.