Homologous recombination articles from across Nature Portfolio

Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.

Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.

R-loop accumulation at transcription sites poses a persistent threat to genome integrity. Here the authors demonstrate a role for PSIP1/LEDGF protein in reducing R-loop levels at the site of transcription and preventing transcription replication conflict to maintain genome integrity.

DNA double-strand breaks (DSBs) are highly mutagenic making them central to many pathologies. Here, the authors developed a highly sensitive sequencing approach to study DSB mutagenesis, yielding insights into mutagenic outcomes and characterising their underlying mechanisms.

Increasing evidence links RNA methyltransferases to DNA damage repair. METTL16 is now shown to antagonize homologous recombination by preventing DNA-end resection via MRE11. Thus, METTL16 may represent a cancer vulnerability that can be used to identify patients able to benefit from combination therapies with DNA-damaging agents.

Emerging findings provide compelling evidence that the BRCA1-binding partner BARD1 contributes yet further to BRCA1 function. BARD1 is crucial for positioning the E2 ubiquitin-conjugating enzyme that confers specificity of its ligase to residues on histone H2A, and BARD1 also promotes DNA damage–induced chromatin recruitment through an interaction with ubiquitin-conjugated Lys13 or Lys15 of H2A on the nucleosome core particle.

Replication stress fuels chromosomal instability, tumor heterogeneity and therapy resistance. The Sonic hedgehog pathway is now linked to an unorthodox form of replication stress in cerebellar granular-cell progenitors through deregulated firing of DNA replication origins, with implications for the pathogenesis, genomic instability and treatment of medulloblastoma.

Cyclic GMP–AMP synthase (cGAS) inhibits DNA damage repair in the nucleus and thereby promotes tumorigenesis.