RECQ Helicases: Bloom, Werner and Genome Maintenance

What These Helicases Do

RECQ helicases resolve structures such as G-quadruplexes, displacement loops, stalled forks and recombination intermediates. By dissolving double Holliday junctions, BLM suppresses crossover recombination, which limits loss of heterozygosity.

Their substrates sit at the junction of replication and recombination, so RECQ loss tends to produce chromosome instability rather than a single defined mutational signature.

Three Distinct Syndromes

Biallelic BLM loss causes Bloom syndrome: growth restriction, sun sensitivity, and a broad, early cancer predisposition, with a diagnostic excess of sister chromatid exchanges. Biallelic WRN loss causes Werner syndrome, a segmental premature-ageing disorder with sarcomas and other cancers. RECQL4 variants underlie Rothmund-Thomson syndrome and confer osteosarcoma risk.

That the same gene family produces such different phenotypes reflects the non-redundant roles of individual helicases.

WRN as a Synthetic-Lethal Target

Multiple screens found that cancer cells with microsatellite instability depend on WRN helicase activity, apparently because expanded TA-dinucleotide repeats form secondary structures that require WRN to resolve during replication.

WRN inhibitors are in clinical development for MSI-high tumours. This is an active investigational area, and the dependency is specific to the mismatch-repair-deficient context rather than a general feature of cancer.

Testing and the WRN Opportunity

For the inherited syndromes, diagnosis rests on clinical features plus targeted gene testing, with the sister-chromatid-exchange assay still used for Bloom syndrome. Confirmation matters because it changes cancer surveillance and, in some contexts, chemotherapy and radiation tolerance.

On the tumour side, the actionable item is microsatellite-instability status: an MSI-high result now flags a possible WRN dependency, and WRN inhibitors are being tested specifically in that group. A RECQ-family variant found incidentally on a tumour panel, by contrast, rarely changes management.

Key Takeaways

• ·RECQ helicases resolve DNA structures that arise in replication and recombination.
• ·BLM, WRN and RECQL4 loss cause Bloom, Werner and Rothmund-Thomson syndromes respectively.
• ·MSI-high cancers show a WRN dependency now being tested therapeutically.