Journal article
Clustered and genome‐wide transient mutagenesis in human cancers: Hypermutation without permanent mutators or loss of fitness
BioEssays, Vol.36(4), pp.382-393
04/2014
Handle:
https://hdl.handle.net/2376/101739
PMCID: PMC4145046
PMID: 24615916
Abstract
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.
Some environmental agents and APOBEC cytidine deaminases result in transient hypermutation by causing lesions in ssDNA regions within double strand break repair intermediates and at replication forks. In human cancers such multiple lesions produce mutation clusters, also termed kataegis. Hypermutation of multiple simultaneously formed ssDNA regions may accelerate cancer development.
Metrics
8 Record Views
Details
- Title
- Clustered and genome‐wide transient mutagenesis in human cancers: Hypermutation without permanent mutators or loss of fitness
- Creators
- Steven A Roberts - National Institute of Environmental Health SciencesDmitry A Gordenin - National Institute of Environmental Health Sciences
- Publication Details
- BioEssays, Vol.36(4), pp.382-393
- Academic Unit
- Molecular Biosciences, School of
- Number of pages
- 12
- Grant note
- NIH, National Institute of Environmental Health Sciences (ES065073) NIH Pathway to Independence Award (K99ES022633‐01)
- Identifiers
- 99900546621201842
- Language
- English
- Resource Type
- Journal article