Deficiency in the repair of UV-induced DNA damage in human skin fibroblasts compromised for the ATM gene.
Ataxia-telangiectasia (A-T), is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. A-T cells exhibit a greatly decreased survival and a reduction in DNA synthesis inhibition as well as p53 induction in response to ionizing radiation. Occasionally, some strains of A-T cells have been reported to manifest a slightly enhanced sensitivity with no consistent observations of a deficiency in either cell cycle control or the repair of DNA damage after treatment with ultraviolet (UV) light. In the present study it is shown that skin fibroblasts from four A-T patients, compared with the control, display enhanced sensitivity to the killing effect of UV-light, moderate radioresistant DNA synthesis, and a reduction in viral recovery in the host cell reactivation (HCR) assay. PCR based analysis indicated that three of these UV-sensitive A-T cell strains bear a large deletion in the ATM gene, and no ATM polypeptide was detected in their cell free extracts. Moreover, it is shown that, in non-replicative conditions, these A-T cells are less efficient than normal cells in repairing the T4 endonuclease V sensitive sites. These results constitute the first clear evidence showing the deficiency of A-T cells in the repair of UV-induced DNA damage, and provide further information on the relationship between cell cycle control and DNA repair in human cells.
Hannan
Mohammed A
MA
King Faisal Specialist Hospital and Research Center, Biological and Medical Research Department, MBC 03-66, Riyadh 11211, Saudi Arabia.
Hellani
Ali
A
Al-Khodairy
Fahad M
FM
Kunhi
Mohammed
M
Siddiqui
Yunis
Y
Al-Yussef
Noujud
N
Pangue-Cruz
Nancy
N
Siewertsen
Monica
M
Al-Ahdal
Mohammed N
MN
Aboussekhra
Abdelilah
A
D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D001706:Biopsy; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects*; D004261:DNA Replication / Q000528:radiation effects; D004268:DNA-Binding Proteins; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000473:pathology / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D007700:Kinetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
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