• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

Delineation of WRN helicase function with EXO1 in the replicational stress response.

The WRN gene defective in the premature aging disorder Werner syndrome encodes a helicase/exonuclease. We examined the ability of WRN to rescue DNA damage sensitivity of a yeast mutant defective in the Rad50 subunit of Mre11-Rad50-Xrs2 nuclease complex implicated in homologous recombination repair. Genetic studies revealed WRN operates in a yEXO1-dependent pathway to rescue rad50 sensitivity to methylmethane sulfonate (MMS). WRN helicase, but not exonuclease, is required for MMS resistance. WRN missense mutations in helicase or RecQ C-terminal domains interfered with the ability of WRN to rescue rad50 MMS sensitivity. WRN does not rescue rad50 ionizing radiation (IR) sensitivity, suggesting that WRN, in collaboration with yEXO1, is tailored to relieve replicational stress imposed by alkylated base damage. WRN and yEXO1 are associated with each other in vivo. Purified WRN stimulates hEXO1 nuclease activity on DNA substrates associated with a stalled or regressed replication fork. We propose WRN helicase operates in an EXO1-dependent pathway to help cells survive replicational stress. In contrast to WRN, BLM helicase defective in Bloom's syndrome failed to rescue rad50 MMS sensitivity, but partially restored IR resistance, suggesting a delineation of function by the human RecQ helicases.

Pubmed ID: 20447876

Authors

  • Aggarwal M
  • Sommers JA
  • Morris C
  • Brosh RM

Journal

DNA repair

Publication Data

July 1, 2010

Associated Grants

  • Agency: Intramural NIH HHS, Id: Z01 AG000752-01
  • Agency: Intramural NIH HHS, Id: ZIA AG000741-09

Mesh Terms

  • DNA Repair
  • DNA Repair Enzymes
  • DNA Replication
  • DNA-Binding Proteins
  • Drug Resistance, Fungal
  • Exodeoxyribonucleases
  • Genetic Complementation Test
  • Humans
  • Methyl Methanesulfonate
  • RecQ Helicases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Stress, Physiological