Login / Signup

Rescue of collapsed replication forks is dependent on NSMCE2 to prevent mitotic DNA damage.

Kelvin W PondChristelle de RentyMary K YagleNathan A Ellis
Published in: PLoS genetics (2019)
NSMCE2 is an E3 SUMO ligase and a subunit of the SMC5/6 complex that associates with the replication fork and protects against genomic instability. Here, we study the fate of collapsed replication forks generated by prolonged hydroxyurea treatment in human NSMCE2-deficient cells. Double strand breaks accumulate during rescue by converging forks in normal cells but not in NSMCE2-deficient cells. Un-rescued forks persist into mitosis, leading to increased mitotic DNA damage. Excess RAD51 accumulates and persists at collapsed forks in NSMCE2-deficient cells, possibly due to lack of BLM recruitment to stalled forks. Despite failure of BLM to accumulate at stalled forks, NSMCE2-deficient cells exhibit lower levels of hydroxyurea-induced sister chromatid exchange. In cells deficient in both NSMCE2 and BLM, hydroxyurea-induced double strand breaks and sister chromatid exchange resembled levels found in NSCME2-deficient cells. We conclude that the rescue of collapsed forks by converging forks is dependent on NSMCE2.
Keyphrases
  • induced apoptosis
  • dna damage
  • cell cycle arrest
  • oxidative stress
  • endoplasmic reticulum stress
  • endothelial cells
  • dna repair
  • cell proliferation
  • copy number
  • drug induced