Heterozygous ATR mutations in mismatch repair-deficient cancer cells have functional significance.
ATR (ataxia telangiectasia and Rad3-related) function is necessary for the proper response to commonly used chemotherapeutic agents. Heterozygous truncating mutations in exon 10 of the ATR gene have been described in numerous cancers exhibiting microsatellite instability. We show that truncating mutations of ATR are capable of acting in a dominant-negative manner to abrogate ATR-dependent Chk1 phosphorylation and cell-cycle arrests after DNA damage. In addition, endometrial cell lines harboring ATR mutations are defective for ATR-dependent responses. These findings imply that ATR mutations play an important role in the development and clinical behavior of a subset of microsatellite instability-positive endometrial, colon, and stomach cancers.
Lewis
Kriste A
KA
Department of Obstetrics and Gynecology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Mullany
Sally
S
Thomas
Bijoy
B
Chien
Jeremy
J
Loewen
Ralitsa
R
Shridhar
Viji
V
Cliby
William A
WA
D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D020137:Base Pair Mismatch / Q000235:genetics*; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D020014:K562 Cells; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D018797:Cell Cycle Proteins; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases