Fumarase is involved in DNA double-strand break resection through a functional interaction with Sae2

Michael Leshets, Dharanidharan Ramamurthy, Michael Lisby, Norbert Lehming, Ophry Pines*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


One of the most severe forms of DNA damage is the double-strand break (DSB). Failure to properly repair the damage can cause mutation, gross chromosomal rearrangements and lead to the development of cancer. In eukaryotes, homologous recombination (HR) and non-homologous end joining (NHEJ) are the main DSB repair pathways. Fumarase is a mitochondrial enzyme which functions in the tricarboxylic acid cycle. Intriguingly, the enzyme can be readily detected in the cytosolic compartment of all organisms examined, and we have shown that cytosolic fumarase participates in the DNA damage response towards DSBs. In human cells, fumarase was shown to be involved in NHEJ, but it is still unclear whether fumarase is also important for the HR pathway. Here we show that the depletion of cytosolic fumarase in yeast prolongs the presence of Mre11 at the DSBs, and decreases the kinetics of repair by the HR pathway. Overexpression of Sae2 endonuclease reduced the DSB sensitivity of the cytosolic fumarase depleted yeast, suggesting that Sae2 and fumarase functionally interact. Our results also suggest that Sae2 and cytosolic fumarase physically interact in vivo. Sae2 has been shown to be important for the DSB resection process, which is essential for the repair of DSBs by the HR pathway. Depletion of cytosolic fumarase inhibited DSB resection, while the overexpression of cytosolic fumarase or Sae2 restored resection. Together with our finding that cytosolic fumarase depletion reduces Sae2 cellular amounts, our results suggest that cytosolic fumarase is important for the DSB resection process by regulating Sae2 levels.

Original languageAmerican English
Pages (from-to)697-712
Number of pages16
JournalCurrent Genetics
Issue number3
StatePublished - 1 Jun 2018

Bibliographical note

Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany, part of Springer Nature.


  • DNA damage response
  • Double-strand break resection
  • Fumarase
  • HR repair pathway
  • Homologous recombination
  • Sae2


Dive into the research topics of 'Fumarase is involved in DNA double-strand break resection through a functional interaction with Sae2'. Together they form a unique fingerprint.

Cite this