Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability

Masnovo, C., Paleiov, Z., Dovrat, D. et al. Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability. Nat Commun 15, 10532 (2024). doi:10.1038/s41467-024-54977-6  

Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA)n repeat instability in a budding yeast model by loss of proper CMG helicase interaction. When repair is inefficient, such as in the case of RPA depletion, breakage of under-replicated repetitive DNA can occur during G2/M, leading to loss of essential genes and cell death. We hypothesize that the CMG-Mcm10 interaction promotes replication through hard-to-replicate regions, assuring genome stability and cell survival.

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α. Hong Wang, … , Fumito Ichinose, Vamsi K. Mootha. Published December 2, 2024. J Clin Invest. 2024;134(23):e185569. doi:10.1172/JCI185569. 

Our results provide preclinical proof of concept that simultaneously enhancing Hb oxygen affinity while antagonizing HIF-2α can mimic the effects of continuous hypoxic breathing for therapeutic benefit. The regimen did not confer as impressive a lifespan rescue as continuous breathing of 11% oxygen, probably because GBT440 has a short half-life (6), and for practical reasons, we treated the mice five weekdays per week. Future studies in humans are required to evaluate the safety of this combination, given that hypoxia can be associated with acute and long-term side effects. Such safety studies could pave the path for first-in-human “hypoxia-in-a-pill” trials in patients with mitochondrial disease.