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Author Spotlight: Unveiling the Role of SNF2L in Replication Fork Stability and Genome Duplication
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Author Spotlight: Unveiling the Role of SNF2L in Replication Fork Stability and Genome Duplication

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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
PubMed

Insights

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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