Breakpoints in the ataxia telangiectasia gene arise at the RGYW somatic hypermutation motif.
The mature sporadic T-cell malignancy, T-cell prolymphocytic leukemia (T-PLL) is remarkable for frequently harbouring somatic mutations of the Ataxia Telangiectasia (A-T) gene, ATM. Because some data suggest ATM is frequently rearranged in T-PLL, it was decided to investigate such rearrangements in detail by cloning breakpoints. Among 17 T-PLL tumour samples, three rearrangements were detected by Southern blotting. Two cases harboured a unique type of intragenic duplication in which breakpoints arose at the consensus sequence RGYW/WRCY. The third case harboured a large deletion terminating within the ATM gene. Also, 13 T-cell acute lymphoblastic leukemia (T-ALL) samples were examined and one sample harboured a deletion- insertion with the RGYW motif at the breakpoint in ATM. This is the first known deleterious mutation detected in ATM in T-ALL. Interestingly, the RGYW motif is the signal for a cell-cycle regulated DNA double strand break (DSB) that initiates somatic hypermutation of immunoglobulin and, probably, T-cell receptor genes. The structures of the ATM duplications suggest they may arise from an error in somatic hypermutation. We suggest that aberrant components of somatic hypermutation may contribute to the defective DSB repair characteristic of cancer.
Bradshaw
Paul S
PS
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, Surrey, UK.
Condie
Alison
A
Matutes
Estella
E
Catovsky
Daniel
D
Yuille
Martin R
MR
D000293:Adolescent; D000328:Adult; D000368:Aged; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002648:Child; D019457:Chromosome Breakage / Q000235:genetics*; D016384:Consensus Sequence / Q000235:genetics*; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases