Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM.
Chromosome aberrations, genomic instability, and cancer predisposition are hallmarks of a number of syndromes in which the defective genes recognize and/or repair DNA damage or are involved in some aspect of DNA processing. We report here direct interaction between BLM, mutated in Bloom's Syndrome (BS), and ATM, mutated is ataxia-telangiectasia, and we have mapped the sites of interaction. Full-length BLM cDNA corrected sister chromatid exchange (SCE) and radiosensitivity in BS cells. Mitotic phosphorylation of BLM was partially dependent on ATM, and phosphorylation sites on BLM were identified. A phosphospecific antibody against one of these sites (Thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. Stable cell lines expressing phosphorylation site mutants failed to correct radiosensitivity in BS cells but corrected SCE. These mutants also sensitized normal control cells to radiation and increased radiation-induced chromosome aberrations but did not cause SCE numbers to increase. These data suggest that ATM and BLM function together in recognizing abnormal DNA structures by direct interaction and that these phosphorylation sites in BLM are important for radiosensitivity status but not for SCE frequency.
Beamish
Heather
H
Queensland Cancer Fund Research Laboratories, The Queensland Institute of Medical Research, P. O. Royal Brisbane Hospital, Herston, Brisbane, Qld 4029, Australia.
Kedar
Padmini
P
Kaneko
Hideo
H
Chen
Philip
P
Fukao
Toshiyuki
T
Peng
Cheng
C
Beresten
Sergei
S
Gueven
Nuri
N
Purdie
David
D
Lees-Miller
Susan
S
Ellis
Nathan
N
Kondo
Naomi
N
Lavin
Martin F
MF
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000502:physiology*; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001816:Bloom Syndrome / Q000235:genetics*; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000528:radiation effects; D004265:DNA Helicases / Q000737:chemistry / Q000502:physiology*; D004268:DNA-Binding Proteins; D006801:Humans; D008938:Mitosis; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000502:physiology*; D011836:Radiation Tolerance; D053484:RecQ Helicases; D012854:Sister Chromatid Exchange; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases