Many of the regulators of the homologous recombination (HR) DNA-repair pathway, such as BRCA2 and the RecQ helicases WRN and BLM, are often associated with cancer owing to unproductive HR repair and genomic instability. Reporting in Cell, Simon Boulton and colleagues have identified a new HR gene in humans that may also be deregulated in cancer.

In Saccharomyces cerevisiae, the helicase Srs2 antagonizes the initial steps of HR, and srs2 mutants exhibit spontaneous recombination and sensitivity to DNA-damaging agents that produce HR substrates, similarly to the loss of other HR genes. The homologue of Srs2 in higher eukaryotes has not yet been identified, so Barber and colleagues conducted a candidate-based synthetic lethality screen in Caenorhabditis elegans. The authors identified a mutant of F25H2.13 — which they named rtel-1 — as a putative Srs2 homologue. The single mutants were viable but their life cycle was retarded, and they exhibited phenotypes that were consistent with genomic instability arising from unrepaired DNA damage. Moreover, double mutants with ablated HR-associated DNA-damage repair or helicase genes showed significant accumulation of foci that contained the HR protein RAD-51. Indeed, consistent with Srs2, the authors found that rtel-1 mutants exhibited an approximately fourfold increase in meiotic crossing over (for which HR is required) and sensitivity to DNA-damaging agents that cause intrastrand crosslinks, (which are substrates for HR), indicating that RTEL-1 antagonizes HR.

So, is Srs2 conserved in humans? Barber and colleagues identified RTEL1 in humans and used small interfering RNA in HeLa cells to show that HR increased by approximately fourfold and cells were sensitive to intrastrand crosslink-inducing drugs, indicating that RTEL1 suppresses HR in humans. Moreover, using an in vitro HR assay, they showed that RTEL1 reversed an early stage in HR. Therefore, although there are some differences, RTEL1 in both humans and C. elegans seems to be a functional analogue of Srs2.

RTEL1 is within a locus containing three other genes that is overexpressed in some gastrointestinal tumours, and the authors posit that increased expression of RTEL1 could suppress productive HR, thereby mimicking the effects of oncogenic HR mutants. Indeed, analysis of tumour samples might reveal a common trait of RTEL1 deregulation in cancer.