Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition

Oncogene. 2002 Mar 27;21(13):2079-88. doi: 10.1038/sj.onc.1205246.

Abstract

Bloom's syndrome (BS) arises through mutations in both copies of the BLM gene that encodes a RecQ 3'-5' DNA helicase. BS patients are predisposed to developing all the cancers that affect the general population, and BS cells exhibit marked genetic instability. We showed recently that BLM protein contributes to the cellular response to ionizing radiation by acting as downstream ATM kinase effector. We now show that following UVC treatment, BLM-deficient cells exhibit a reduction in the number of replicative cells, a partial escape from the G2/M cell cycle checkpoint, and have an altered p21 response. Surprisingly, we found that hydroxyurea-treated BLM-deficient cells exhibit an intact S phase arrest, proper recovery from the S phase arrest, and intact p53 and p21 responses. We also show that the level of BLM falls sharply in response to UVC radiation. This UVC-induced reduction in BLM does not require a functional ATM gene and does not result from a subcellular compartment change. Finally, we demonstrate that exposure to UVC and hydroxyurea treatment both induce BLM phosphorylation via an ATM-independent pathway. These results are discussed in the light of their potential physiological significance with regard to the role of BLM in the cellular pathways activated by UVC radiation or HU-mediated inhibition of DNA synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / deficiency
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Ataxia Telangiectasia Mutated Proteins
  • Bloom Syndrome / genetics
  • Cell Cycle Proteins
  • Cell Division / drug effects
  • Cell Division / radiation effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • DNA / biosynthesis
  • DNA / drug effects*
  • DNA Helicases / deficiency
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Replication / drug effects*
  • DNA Replication / radiation effects*
  • DNA-Binding Proteins
  • Flow Cytometry
  • G2 Phase / drug effects
  • G2 Phase / radiation effects
  • Gene Expression Regulation / radiation effects
  • Humans
  • Hydroxyurea / pharmacology*
  • Mitosis / drug effects
  • Mitosis / radiation effects
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • RecQ Helicases
  • S Phase / drug effects
  • S Phase / radiation effects
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins
  • Ultraviolet Rays*

Substances

  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • DNA
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • Adenosine Triphosphatases
  • Bloom syndrome protein
  • DNA Helicases
  • RecQ Helicases
  • Hydroxyurea