Functional consequences of ATM sequence variants for chromosomal radiosensitivity.
The ATM [for ataxia-telangiectasia (A-T) mutated] protein plays a key role in the detection and cellular response to DNA double-strand breaks. Several single-nucleotide polymorphisms (SNPs) have been described in the ATM gene; however, their association with cancer risk or radiosensitivity remains to be fully established. In this study, the functional consequences of specific ATM SNPs on in vitro radiosensitivity, as assessed by micronuclei (MN) formation, were measured in lymphoblastoid cell lines established from 10 breast cancer (BC) patients carrying different ATM missense SNPs, six A-T patients, six A-T heterozygotes (A-T het), and six normal individuals. The BC, A-T het, and A-T cell line groups showed significantly higher mean levels of MN formation after exposure to ionizing radiation (IR) than did the group containing normal cell lines, with similar levels in the BC and A-T het groups. Within the BC lines studied, the group composed of the six carrying the linked 2572T>C (858F>L) and 3161C>G (1054P>R) variants had a higher level of MN after IR exposure compared to that observed in the remaining four BC or in the normal cell lines. This increase was not related to the constitutive ATM mRNA level, which was similar in these BC and the normal cell lines. Our results indicate that alterations in the ATM gene, including the presence of heterozygous mutations and the 2572C and 3161G variant alleles, are associated with increased in vitro chromosomal radiosensitivity, perhaps by interfering with ATM function in a dominant-negative manner.
Gutiérrez-Enríquez
Sara
S
DNA Repair Group, International Agency for Research on Cancer, Lyon, France.
Fernet
Marie
M
Dörk
Thilo
T
Bremer
Michael
M
Lauge
Anthony
A
Stoppa-Lyonnet
Dominique
D
Moullan
Norman
N
Angèle
Sandra
S
Hall
Janet
J
D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002875:Chromosomes / Q000528:radiation effects*; D004247:DNA / Q000235:genetics / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D014644:Genetic Variation / Q000235:genetics* / Q000502:physiology; D004854:Herpesvirus 4, Human; D006579:Heterozygote; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000473:pathology / Q000821:virology; D048629:Micronuclei, Chromosome-Defective / Q000235:genetics / Q000528:radiation effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases