The single-stranded DNA-binding factor SUB1/PC4 alleviates replication stress at telomeres and is a vulnerability of ALT cancer cells.

To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms. In 10 to 15% of cancers, this is enabled by recombination-based alternative lengthening of telomeres pathways (ALT). ALT cells display several hallmarks including heterogeneous telomere length, extrachromosomal telomeric repeats, and ALT-associated PML bodies.

SMARCAL1 ubiquitylation controls its association with RPA-coated ssDNA and promotes replication fork stability.

Impediments in replication fork progression cause genomic instability, mutagenesis, and severe pathologies. At stalled forks, RPA-coated single-stranded DNA (ssDNA) activates the ATR kinase and directs fork remodeling, 2 key early events of the replication stress response. RFWD3, a recently described Fanconi anemia (FA) ubiquitin ligase, associates with RPA and promotes its ubiquitylation, facilitating late steps of homologous recombination (HR).

The mutational impact of Illudin S on human cells.

Illudin S (ILS) is a fungal sesquiterpene secondary metabolite with potent genotoxic and cytotoxic properties. Early genetic studies and more recent genome-wide CRISPR screens showed that Illudin-induced lesions are preferentially repaired by transcription-coupled nucleotide excision repair (TC-NER) with some contribution from post-replication repair pathways. In line with these results, Irofulven, a semi-synthetic ILS analog was recently shown to be particularly effective on cell lines and patient-derived xenografts with impaired NER (e.