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C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer
Abhishek Bharadwaj Sharma1, Muhammad Khairul Ramlee1, Joel Kosmin1
1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.
Nature Communications
|August 17, 2023
Summary
Researchers found C16orf72 is crucial for repairing DNA replication stress and works with PARP1/2. This discovery reveals a new pathway that helps cells resist PARP inhibitors, impacting cancer therapy.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The synthetic lethality of PARP inhibitors (PARP1/PARP2) in homologous recombination (HR)-deficient cells is known.
- However, other synthetic lethal interactions with PARP1/PARP2 disruption remain unclear.
Purpose of the Study:
- To identify novel genes synthetically lethal with PARP1/2 disruption.
- To elucidate the mechanisms underlying these interactions and their role in genome stability and drug resistance.
Main Methods:
- Conducted a genome-wide screen to identify genes synthetic lethal with PARP1/2 disruption.
- Investigated the function of identified genes, specifically C16orf72, in response to replication stress.
- Analyzed the interaction of C16orf72 with other proteins like BRCA1 and Senataxin.
Main Results:
- Identified C16orf72 (also known as HAPSTR1/TAPR1) as a novel modulator of replication-associated R-loops.
- C16orf72 is essential for replication fork restart, DNA damage suppression, and genome stability under replication stress.
- C16orf72 and PARP1/2 act in parallel pathways to reduce DNA:RNA hybrids at stalled replication forks.
- C16orf72 interacts with BRCA1 and Senataxin to facilitate their recruitment to RNA:DNA hybrids, conferring PARP inhibitor resistance.
Conclusions:
- Discovered a C16orf72/Senataxin/BRCA1-dependent pathway that suppresses R-loop accumulation during replication.
- This pathway is critical for maintaining genome stability and confers resistance to PARP inhibitors.
- Highlights C16orf72 as a potential therapeutic target in cancer treatment.
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