Somatic microindels in human cancer: the insertions are highly error-prone and derive from nearby but not adjacent sense and antisense templates.
Somatic microindels (microdeletions with microinsertions) have been studied in normal mouse tissues using the Big Blue lacI transgenic mutation detection system. Here we analyze microindels in human cancers using an endogenous and transcribed gene, the TP53 gene. Microindel frequency, the enhancement of 1-2 microindels and other features are generally similar to that observed in the non-transcribed lacI gene in normal mouse tissues. The current larger sample of somatic microindels reveals recurroids: mutations in which deletions are identical and the co-localized insertion is similar. The data reveal that the inserted sequences derive from nearby but not adjacent sequences in contrast to the slippage that characterizes the great majority of pure microinsertions. The microindel inserted sequences derive from a template on the sense or antisense strand with similar frequency. The estimated error rate of the insertion process of 13% per bp is by far the largest reported in vivo, with the possible exception of somatic hypermutation in the immunoglobulin gene. The data constrain possible mechanisms of microindels and raise the question of whether microindels are 'scars' from the bypass of large DNA adducts by a translesional polymerase, e.g. the 'Tarzan model' presented herein.
Scaringe
William A
WA
Department of Molecular Genetics, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
Li
Kai
K
Gu
Dongqing
D
Gonzalez
Kelly D
KD
Chen
Zhenbin
Z
Hill
Kathleen A
KA
Sommer
Steve S
SS
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D004252:DNA Mutational Analysis; D016373:DNA, Antisense / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D056968:Lac Repressors; D051379:Mice; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009369:Neoplasms / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D013698:Templates, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D001426:Bacterial Proteins; D016373:DNA, Antisense; D056968:Lac Repressors; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53