A kinase that arrests cells in response to nuclear DNA damage also safeguards the inheritance of mitochondrial DNA (mtDNA), Crider et al. report.
mtDNA encodes many of the proteins required for mitochondrial respiration. Budding yeast lacking mtDNA can still survive, but Crider et al. found that these cells arrested during the cell cycle, often failing to progress from G1 into S phase.
This arrest wasn’t due to defects in the electron transport chain or ATP synthesis, because deleting a subunit of cytochrome c oxidase or inhibiting ATP synthase had no effect on the cell cycle. Yeast also entered S phase promptly if their mtDNA was replaced by junk, noncoding sequences, suggesting that arrest is triggered by the absence of DNA from mitochondria rather than the loss of any specific gene.
Rad53 is a protein kinase that delays S phase entry when nuclear DNA is damaged and is also required for mtDNA maintenance in yeast and mammalian cells. Crider et al. found that Rad53 was activated by the loss of mtDNA and that yeast lacking the kinase no longer arrested in G1/S. The researchers now want to investigate how mitochondria sense the absence of mtDNA and signal to Rad53 to initiate what senior author Liza Pon calls a “mtDNA inheritance checkpoint.” Pon is also intrigued by the idea that mutations in the Rad53 pathway may cause the changes in mtDNA copy number that are often seen in tumor samples, which may, in turn, lead to alterations in cancer cell metabolism.
