page_title: Kataegis
section_title: APOBEC enzyme family (C→T mutations)
hierarchical_section_title: Kataegis / Mechanism / APOBEC enzyme family (C→T mutations)
caption_attribution_description: English: APOBEC-2 is a member of the APOBEC (apolipoprotein B messenger RNA-editing enzyme catalytic) family. Rendering based on PDB ID: 2NYT.
context_page_description: In molecular biology, kataegis describes a pattern of localized hypermutations identified in some cancer genomes, in which a large number of highly-patterned basepair mutations occur in a small region of DNA. The mutational clusters are usually several hundred basepairs long, alternating between a long range of C→T substitutional pattern and a long range of G→A substitutional pattern. This suggests that kataegis is carried out on only one of the two template strands of DNA during replication. Compared to other cancer-related mutations, such as chromothripsis, kataegis is more commonly seen; it is not an accumulative process but likely happens during one cycle of replication.
  The term kataegis is derived from the ancient Greek word for "thunderstorm". It was first used by scientists at the Wellcome Trust Sanger Institute to describe their observations of breast cancer cells. In the process of mapping mutation clusters across the genome, they used a visualization tool called "rainfall plots", as shown on the picture on the right, with which they observed a clustering pattern for kataegis.
context_section_description: APOBEC family is a group of cytidine deaminase enzymes that plays an important role in immune system. Its major function is to induce genetic mutations in antibodies, which need a huge variety of genes in order to bind to different antigens. APOBEC family can also  protect against the infection of RNA retroviruses and retrotransposons. In a single-strand DNA (ssDNA), APOBEC can transfer an amine group from a cytosine(C) and turn it into a uracil(U); such mutations can deaminate the viral gene and terminate the retro-transcription process that codes RNA back to DNA.
  As shown in Figure 1, the base mutations in kataegis regions were found to be almost exclusively cytosine to thymine in the context of a TpC dinucleotide(p denotes the phosphoribose backbone). At DNA lesion sites, APOBEC enzyme can have access to long ssDNA and induce a C→U mutations. APOBEC family is processive and can continue to induce multiple mutations in a small region. If this part of DNA is replicated before such mutation is repaired, the mutation gets passed on to the subclones. The original CG pair will become a TA pair after one round of replication, hence the predominantly seen C→T mutation in kataegis.
  Among the APOBEC family, APOBEC3 subfamily are responsible for protection against retroviruses such as HIV(known to be modified by APOBEC3F and APOBEC3G). Since their original functions include editing ssDNA, they are more likely to be responsible for causing large numbers of mutations on human ssDNA. The direct link between the APOBEC deaminases and kataegistic clusters of mutations was recently obtained by expressing hyperactive deaminase in yeast cells. Recent evidence has linked the over-expression of the family member APOBEC3B with multiple human cancers, highlighting its possible contribution to genomic instability and kataegis.
  Meanwhile, activation-induced cytidine deaminase (AID) is shown to  facilitate kataegis formation in human lymphomas. AID's majorly function is to diversify the genes among immune cells. Recent research shows that AID is involved in site-specific mutations in B cell tumor, while APOBEC3 subfamily causes the non-specific, cross-genomic mutations in non-B cell tumor.
caption: Figure 2: APOBEC deaminase for Homo Sapiens. This is a 3D model for APOBEC-2 protein.[4]
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