Hrq1 helicase is a novel member of the RecQ family. Among the five human RecQ helicases, Hrq1 is most homologous to RECQL4 and is conserved in fungal genomes. Recent genetic and biochemical studies have shown that it is a functional gene, involved in the maintenance of genome stability. To better define the roles of Hrq1 in yeast cells, we investigated genetic interactions between HRQ1 and several DNA repair genes. Based on DNA damage sensitivities induced by 4-nitroquinoline-1-oxide (4-NQO) or cisplatin, RAD4 was found to be epistatic to HRQ1. On the other hand, mutant strains defective in either homologous recombination (HR) or post-replication repair (PRR) became more sensitive by additional deletion of HRQ1, indicating that HRQ1 functions in the RAD4-dependent nucleotide excision repair (NER) pathway independent of HR or PRR. In support of this, yeast two-hybrid analysis showed that Hrq1 interacted with Rad4, which was enhanced by DNA damage. Overexpression of Hrq1K318A helicase-deficient protein rendered mutant cells more sensitive to 4-NQO and cisplatin, suggesting that helicase activity is required for the proper function of Hrq1 in NER.

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Maintenance of genome stability in eukaryotes involves a number of conserved proteins, including RecQ helicases, which play multiple roles at various steps in homologous recombination and DNA repair pathways. Sgs1 has been described as the only RecQ helicase in lower eukaryotes. However, recent studies revealed the presence of a second RecQ helicase, Hrq1, which is most homologous to human RECQL4. Here we show that hrq1Δ mutation resulted in increased mitotic recombination and spontaneous mutation in Saccharomyces cerevisiae, and sgs1Δ mutation had additive effects on the phenotypes of hrq1Δ. We also observed that the hrq1Δ mutant was sensitive to 4-nitroquinoline 1-oxide and cisplatin, which was not complemented by overexpression of Sgs1. In addition, the hrq1Δ sgs1Δ double mutant displayed synthetic growth defect as well as a shortened chronological life span compared with the respective single mutants. Analysis of the type of age-dependent Can(r) mutations revealed that only point mutations were found in hrq1Δ, whereas significant numbers of gross deletion mutations were found in sgs1Δ. Our results suggest that Hrq1 is involved in recombination and DNA repair pathways in S. cerevisiae independent of Sgs1.

Objective: To determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in DAPA-HF varied by background glucose-lowering therapy (GLT). Research design and methods: We examined the effect of study treatment by the use or not of GLT, and by GLT classes and combinations. The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. Results: In the 2139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use/no use (hazard ratio 0.72 [95%CI 0.58-0.88] versus 0.86 [0.60-1.23]; P-interaction=0.39) and across GLT classes. Conclusions: In DAPA-HF, dapagliflozin improved outcomes irrespective of use/no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.

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