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Transient hypermutability, chromothripsis and replication-based mechanisms in the generation of concurrent clustered mutations

Chen, Jian-Min, Férec, Claude and Cooper, David Neil 2012. Transient hypermutability, chromothripsis and replication-based mechanisms in the generation of concurrent clustered mutations. Mutation Research/Reviews in Mutation Research 750 (1) , pp. 52-59. 10.1016/j.mrrev.2011.10.002

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Abstract

Clustered mutations may be broadly defined as the presence of two or more mutations within a spatially localized genomic region on a single chromosome. Known instances vary in terms of both the number and type of the component mutations, ranging from two closely spaced point mutations to tens or even hundreds of genomic rearrangements. Although clustered mutations can represent the observable net result of independent lesions sequentially acquired over multiple cell cycles, they can also be generated in a simultaneous or quasi-simultaneous manner within a single cell cycle. This review focuses on those mechanisms known to underlie the latter type. Both gene conversion and transient hypermutability are capable of generating closely spaced multiple mutations. However, a recently described phenomenon in human cancer cells, known as 'chromothripsis', has provided convincing evidence that tens to hundreds of genomic rearrangements can sometimes be generated simultaneously via a single catastrophic event. The distinctive genomic features observed in the derivative chromosomes, together with the highly characteristic junction sequences, point to non-homologous end joining (NHEJ) as being the likely underlying mutational mechanism. By contrast, replication-based mechanisms such as microhomology-mediated break-induced replication (MMBIR) which involves serial replication slippage or serial template switching probably account for those complex genomic rearrangements that comprise multiple duplications and/or triplications.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
Uncontrolled Keywords: Chromothripsis; Complex genomic rearrangement; Multiple mutation; Mutational mechanisms; Non-homologous end joining; Transient hypermutability
Publisher: Elsevier
ISSN: 1383-5742
Last Modified: 04 Jun 2017 03:44
URI: http://orca.cf.ac.uk/id/eprint/25629

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