Kataegis

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Figure 1: Rainfall plot maps the inter-mutational distance of breast cancer genes and tracks the basepair substitution in each mutation. A) shows clustered kataegis pattern in a small region (denoted by the red dots), and B) shows kataegis patterns scattered all over the genome. Rainplot for Kataegis in Breast Cancer Genome.jpg
Figure 1: Rainfall plot maps the inter-mutational distance of breast cancer genes and tracks the basepair substitution in each mutation. A) shows clustered kataegis pattern in a small region (denoted by the red dots), and B) shows kataegis patterns scattered all over the genome.

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. [1] 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. [1] 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. [2]

Contents

The term kataegis (καταιγίς) 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. [1]

Mechanism

Regions of kataegis have been shown to be colocalised with regions of somatic genome rearrangements. [1] In these regions, known as the breakpoints, basepairs are more prone to get deleted, substituted, or translocated. Most hypotheses of the kataegis involves errors during the frequent DNA repair at the breakpoints. A collection of enzymes from the DNA repair system will come in to excise the mismatch basepair. When these enzymes try to mend the mutational damage, they unwind DNA into single strands and create lesion regions that do not have a purine/pyrimidine base. Across the lesion region, the bases in the unpaired, single-stranded DNA(ssDNA) are more accessible to the modifying enzyme groups that can cause further damage in the sequence, thus forming the mutational clusters seen in kataegis. [3]

Two enzyme families are assumed to be related to kataegis. The APOBEC("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like") enzyme family causes predominately C→T mutations, and translesional DNA synthesis (TLS) DNA polymerase causes C→G or C→T mutations.[ citation needed ]

APOBEC enzyme family (C→T mutations)

Figure 2: APOBEC deaminase for Homo Sapiens. This is a 3D model for APOBEC-2 protein. Apobec.J.Steinfeld.D.png
Figure 2: APOBEC deaminase for Homo Sapiens. This is a 3D model for APOBEC-2 protein.

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. [5] APOBEC family can also protect against the infection of RNA retroviruses and retrotransposons. [4] 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. [6]

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). [1] 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. [7] If this part of DNA is replicated before such mutation is repaired, the mutation gets passed on to the subclones. [3] [8] The original CG pair will become a TA pair after one round of replication, hence the predominantly seen C→T mutation in kataegis.[ citation needed ]

Among the APOBEC family, APOBEC3 subfamily are responsible for protection against retroviruses such as HIV(known to be modified by APOBEC3F and APOBEC3G). [9] [10] 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. [7] 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. [11]

Meanwhile, activation-induced cytidine deaminase (AID) is shown to facilitate kataegis formation in human lymphomas. [8] 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. [8] [12]

Figure 3: Different errors can occur when TLS DNA Polymerase insert over a lesion. A) Misincorporation of base: a mismatched cytosine(blue) is inserted to pair with an adenine(asterisk). B)Slippage: An extra adenine is inserted into the sequence. C)Hairpin in sequence: polymerase passes by the hairpin in the replication of nascent strand Error-prone TLS DNA Polymerase.gif
Figure 3: Different errors can occur when TLS DNA Polymerase insert over a lesion. A) Misincorporation of base: a mismatched cytosine(blue) is inserted to pair with an adenine(asterisk). B)Slippage: An extra adenine is inserted into the sequence. C)Hairpin in sequence: polymerase passes by the hairpin in the replication of nascent strand

TLS DNA polymerase (C→G and C→T mutations)

Translesional DNA synthesis (TLS) DNA polymerase family brings in the nucleotide to bridge across the abasic sites in DNA lesion. Due to the natural of the function of this enzyme, TLS DNA polymerase has a high error rates. It can slip at sequence or insert A or C base pairs into a distorted region on DNA strand; ss shown in Figure 3, TLS DNA polymerase may cause mutations in many different ways. [3]

Among the TLS DNA polymerases, Rev1 has a mechanism of inserting cytosine into lesion site that does not contain a template. Since Rev1 does not read according to Watson and Crick basepair, it can introduce any random nucleotide into the DNA sequence. In most experimental cases, Rev1 is responsible for the C→G mutation during DNA repair. [3] The effect of Rev1 can be combined with that of the APOBEC family. If the C→U mutation error is detected by its specific glycosylase, the glycosylase will cut the base pair and form an abasic site. Then TLS DNA polymerase can come in and induce C→G in this case. [12] In yeast research data, Rev1 and Rev3 can account for up 98% of basepair substitutions and 95% of UV induced mutations. [13]

Pol ζ is another kind of TLS DNA polymerase that collaborates with Rev1(mostly Rev1p) in the process of forming hypermutations in eukaryotes. Pol ζ is hypothesized to contribute to homologous allele exchanges. It can extend from DNA region distorted or bulged due to mismatches and bypass certain lesion site in DNA. [14] According to research in yeast, Pol ζ can pass different mutations with ~10% efficiency, much more often than the result from other polymerases. When Pol ζ reads pass the mutation sites, the genetic mutations remain and are passed on to the next round of replication. [13]

Clinical Significance

Kataegis is prevalently seen among breast cancer patients, and it is also exists in lung cancers, cervical, head and neck, and bladder cancers, as shown in the results from tracing APOBEC mutation signatures. [3] Understanding the mechanism of how kataegis can be useful for the future research in how cancer has developed. Due to the highly patterned mutations in kataegis, researchers can make statistical models in order to trace the loci that are prone to mutations. [3]

Research have found that kataegis could be a good prognostic indicator for breast cancer patient, that there is a life expectancy difference between patients with kataegis and those without. The specific reason was not clear. Because kataegis causes up-regulation and down-regulation of different factors, it is hypothesized that kataegis might have down-regulated the migration related gene, thus causing the tumor to be less invasive. [15]

See also

Related Research Articles

Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases.

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Molecular lesion</span> Damage to the structure of a biological molecule

A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

<span class="mw-page-title-main">Activation-induced cytidine deaminase</span> Enzyme that creates mutations in DNA

Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the AICDA gene. It creates mutations in DNA by deamination of cytosine base, which turns it into uracil. In other words, it changes a C:G base pair into a U:G mismatch. The cell's DNA replication machinery recognizes the U as a T, and hence C:G is converted to a T:A base pair. During germinal center development of B lymphocytes, AID also generates other types of mutations, such as C:G to A:T. The mechanism by which these other mutations are created is not well understood. It is a member of the APOBEC family.

<span class="mw-page-title-main">Pyrimidine dimer</span> Type of damage to DNA

Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions, commonly associated with direct DNA damage. Ultraviolet light induces the formation of covalent linkages between consecutive bases along the nucleotide chain in the vicinity of their carbon–carbon double bonds. The photo-coupled dimers are fluorescent. The dimerization reaction can also occur among pyrimidine bases in dsRNA —uracil or cytosine. Two common UV products are cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts. These premutagenic lesions alter the structure of the DNA helix and cause non-canonical base pairing. Specifically, adjacent thymines or cytosines in DNA will form a cyclobutane ring when joined together and cause a distortion in the DNA. This distortion prevents replication or transcription machinery beyond the site of the dimerization. Up to 50–100 such reactions per second might occur in a skin cell during exposure to sunlight, but are usually corrected within seconds by photolyase reactivation or nucleotide excision repair. In humans, the most common form of DNA repair is nucleotide excision repair (NER). In contrast, organisms such as bacteria can counterintuitively harvest energy from the sun to fix DNA damage from pyrimidine dimers via photolyase activity. If these lesions are not fixed, polymerase machinery may misread or add in the incorrect nucleotide to the strand. If the damage to the DNA is overwhelming, mutations can arise within the genome of an organism and may lead to the production of cancer cells. Uncorrected lesions can inhibit polymerases, cause misreading during transcription or replication, or lead to arrest of replication. It causes sunburn and it triggers the production of melanin. Pyrimidine dimers are the primary cause of melanomas in humans.

Missense mRNA is a messenger RNA bearing one or more mutated codons that yield polypeptides with an amino acid sequence different from the wild-type or naturally occurring polypeptide. Missense mRNA molecules are created when template DNA strands or the mRNA strands themselves undergo a missense mutation in which a protein coding sequence is mutated and an altered amino acid sequence is coded for.

<span class="mw-page-title-main">APOBEC1</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 also known as C->U-editing enzyme APOBEC-1 is a protein that in humans is encoded by the APOBEC1 gene.

<span class="mw-page-title-main">Cytidine deaminase</span> Protein-coding gene in the species Homo sapiens

Cytidine deaminase is an enzyme that in humans is encoded by the CDA gene.

<span class="mw-page-title-main">APOBEC3F</span> Protein-coding gene in the species Homo sapiens

DNA dC->dU-editing enzyme APOBEC-3F is a protein that in humans is encoded by the APOBEC3F gene.

<span class="mw-page-title-main">REV1</span> Protein-coding gene in the species Homo sapiens

DNA repair protein REV1 is a protein that in humans is encoded by the REV1 gene.

<span class="mw-page-title-main">REV3L</span> Protein-coding gene in the species Homo sapiens

Protein reversionless 3-like (REV3L) also known as DNA polymerase zeta catalytic subunit (POLZ) is an enzyme that in humans is encoded by the REV3L gene.

<span class="mw-page-title-main">APOBEC3A</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A, also known as APOBEC3A, or A3A is a gene of the APOBEC3 family found in humans, non-human primates, and some other mammals. It is a single-domain DNA cytidine deaminase with antiviral effects. While other members of the family such as APOBEC3G are believed to act by editing ssDNA by removing an amino group from cytosine in DNA, introducing a cytosine to uracil change which can ultimately lead to a cytosine to thymine mutation, one study suggests that APOBEC3A can inhibit parvoviruses by another mechanism. The cellular function of APOBEC3A is likely to be the destruction of foreign DNA through extensive deamination of cytosine.Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS. "APOBEC3 proteins mediate the clearance of foreign DNA from human cells". Nature Structural & Molecular Biology. 17 (2): 222–9. doi:10.1038/nsmb.1744. PMC 2921484. PMID 20062055.

<span class="mw-page-title-main">APOBEC3B</span> Protein-coding gene in the species Homo sapiens

Probable DNA dC->dU-editing enzyme APOBEC-3B is a protein that in humans is encoded by the APOBEC3B gene.

<span class="mw-page-title-main">APOBEC</span> Enzyme involved in messenger RNA editing

APOBEC is a family of evolutionarily conserved cytidine deaminases.

<span class="mw-page-title-main">APOBEC3H</span> Protein-coding gene in the species Homo sapiens

DNA dC->dU-editing enzyme APOBEC-3H, also known as Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3H or APOBEC-related protein 10, is a protein that in humans is encoded by the APOBEC3H gene.

Somatic hypermutation is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it, as seen during class switching. A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring. Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers.

DNA Polymerase V is a polymerase enzyme involved in DNA repair mechanisms in bacteria, such as Escherichia coli. It is composed of a UmuD' homodimer and a UmuC monomer, forming the UmuD'2C protein complex. It is part of the Y-family of DNA Polymerases, which are capable of performing DNA translesion synthesis (TLS). Translesion polymerases bypass DNA damage lesions during DNA replication - if a lesion is not repaired or bypassed the replication fork can stall and lead to cell death. However, Y polymerases have low sequence fidelity during replication. When the UmuC and UmuD' proteins were initially discovered in E. coli, they were thought to be agents that inhibit faithful DNA replication and caused DNA synthesis to have high mutation rates after exposure to UV-light. The polymerase function of Pol V was not discovered until the late 1990s when UmuC was successfully extracted, consequent experiments unequivocally proved UmuD'2C is a polymerase. This finding lead to the detection of many Pol V orthologs and the discovery of the Y-family of polymerases.

Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.

References

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  2. ↑ Wang, Edwin (November 2013). "Understanding genomic alterations in cancer genomes using an integrative network approach". Cancer Letters. 340 (2): 261–269. arXiv: 1409.3263 . doi:10.1016/j.canlet.2012.11.050. PMID   23266571. S2CID   32328448.
  3. 1 2 3 4 5 6 Chan, Kin; Gordenin, Dmitry A. (November 23, 2015). "Clusters of Multiple Mutations: Incidence and Molecular Mechanisms". Annual Review of Genetics. 49 (1): 243–267. doi:10.1146/annurev-genet-112414-054714. ISSN   0066-4197. PMC   4710516 . PMID   26631512.
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  5. ↑ Conticello, Silvestro G.; Thomas, Cornelia J. F.; Petersen-Mahrt, Svend K.; Neuberger, Michael S. (February 2005). "Evolution of the AID/APOBEC Family of Polynucleotide (Deoxy)cytidine Deaminases". Molecular Biology and Evolution. 22 (2): 367–377. doi: 10.1093/molbev/msi026 . ISSN   1537-1719. PMID   15496550.
  6. ↑ Smith, Harold C.; Bennett, Ryan P.; Kizilyer, Ayse; McDougall, William M.; Prohaska, Kimberly M. (May 2012). "Functions and regulation of the APOBEC family of proteins". Seminars in Cell & Developmental Biology. 23 (3): 258–268. doi:10.1016/j.semcdb.2011.10.004. PMC   4017262 . PMID   22001110.
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  8. 1 2 3 Casellas, Rafael; Basu, Uttiya; Yewdell, William T.; Chaudhuri, Jayanta; Robbiani, Davide F.; Di Noia, Javier M. (March 2016). "Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity". Nature Reviews Immunology. 16 (3): 164–176. doi:10.1038/nri.2016.2. ISSN   1474-1733. PMC   4871114 . PMID   26898111.
  9. ↑ Cullen, B. R. (February 1, 2006). "Role and Mechanism of Action of the APOBEC3 Family of Antiretroviral Resistance Factors". Journal of Virology. 80 (3): 1067–1076. doi:10.1128/JVI.80.3.1067-1076.2006. ISSN   0022-538X. PMC   1346961 . PMID   16414984.
  10. ↑ Mbisa, J. L.; Bu, W.; Pathak, V. K. (May 15, 2010). "APOBEC3F and APOBEC3G Inhibit HIV-1 DNA Integration by Different Mechanisms". Journal of Virology. 84 (10): 5250–5259. doi:10.1128/JVI.02358-09. ISSN   0022-538X. PMC   2863843 . PMID   20219927.
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  13. 1 2 Lawrence, Christopher W. (June 2002). "Cellular roles of DNA polymerase ζ and Rev1 protein". DNA Repair. 1 (6): 425–435. doi:10.1016/S1568-7864(02)00038-1. PMID   12509231.
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  15. ↑ D’Antonio, Matteo; Tamayo, Pablo; Mesirov, Jill P.; Frazer, Kelly A. (July 2016). "Kataegis Expression Signature in Breast Cancer Is Associated with Late Onset, Better Prognosis, and Higher HER2 Levels". Cell Reports. 16 (3): 672–683. doi:10.1016/j.celrep.2016.06.026. PMC   4972030 . PMID   27373164.

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