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Clustered and genome‐wide transient mutagenesis in human cancers: Hypermutation without permanent mutators or loss of fitness
Author(s) -
Roberts Steven A.,
Gordenin Dmitry A.
Publication year - 2014
Publication title -
bioessays
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.175
H-Index - 184
eISSN - 1521-1878
pISSN - 0265-9247
DOI - 10.1002/bies.201300140
Subject(s) - apobec , somatic hypermutation , mutagenesis , biology , genetics , mutation , mutation rate , phenotype , dna mismatch repair , genome , genome instability , dna repair , mutation accumulation , dna replication , dna damage , dna , gene , b cell , antibody
The gain of a selective advantage in cancer as well as the establishment of complex traits during evolution require multiple genetic alterations, but how these mutations accumulate over time is currently unclear. There is increasing evidence that a mutator phenotype perpetuates the development of many human cancers. While in some cases the increased mutation rate is the result of a genetic disruption of DNA repair and replication or environmental exposures, other evidence suggests that endogenous DNA damage induced by AID/APOBEC cytidine deaminases can result in transient localized hypermutation generating simultaneous, closely spaced (i.e. “clustered”) multiple mutations. Here, we discuss mechanisms that lead to mutation cluster formation, the biological consequences of their formation in cancer and evidence suggesting that APOBEC mutagenesis can also occur genome‐wide. This raises the possibility that dysregulation of these enzymes may enable rapid malignant transformation by increasing mutation rates without the loss of fitness associated with permanent mutators.