Occurrence of multiple mutation is enhanced by Xpc-inactivation in mouse tissues

Abstract

Multiple mutation meaning two or more mutations in a single gene or DNA is observed at unexpectedly high frequency in normal tissues. It is assumed to be one of the indices of genomic instability called mutator phenotype that might contribute in changing normal cells to cancer cells, because cancer cells contain many mutations. Here we report that the frequency of multiple mutation is elevated in Xpc-deficient mice when they get old. Age-dependent accumulation of spontaneous mutation in spleen, liver, heart and lung was accelerated in Xpc(-/-) mice as was judged by mutation on the transgenic lacZ gene. The acceleration was also observed in spleen and liver of old Xpc(+/-) mice indicating tissue-specific haploinsufficiency. Sequencing of the mutated lacZ genes revealed that the frequency of multiple mutation was elevated in old Xpc-deficient mice. The distribution of different types of mutations (spectrum) found in the multiple mutations was distinct from that of single mutations. The frequency of base substitution at A:T was higher in multiple mutations. The two multiple mutations among 20 found in old Xpc-deficient mice revealed as many as 4 alterations within a short stretch of DNA sequence. They might be produced by error-prone TLS DNA polymerases, because some of the TLS polymerases are reported to make mistakes more than once within a small range of DNA.