**5.2 Epigenetic alterations due to chromosome remodeling and histone modification**

The miRNA is synthesized as primary non-coding RNA these are then processed into mature effective ones which can alter expression of its target genes. On those target genes it influences the methylation status in the promoters and we know that the methylation status of promoters are related to their expression levels or they can directly target epigenetic factors, such as DNA methyltransferases or histone deacetylases, regulating chromatin structure for altered expression. Some genes of mismatch excision repair like MLH1, MSH2, and MSH6 are inactivated by such process, by the action of miR-155 (**Table 1**) [45].

Low expression of miRNA-15 suppresses promoter activity of BRCA1 by recruiting an enhanceosome mediated by HMGA1 [46]. miRNA-16 influence transcriptional activation of HMGA2 protein that again suppress ERCC1, is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. HMGA (High Mobility Group proteins with AT


#### **Table 1.**

*DNA repair pathway genes affected in various ways in cancer.*

hook) code for a chromatin-associated protein that can modulate transcription by altering the chromatin architecture, HMGA1 and HMGA2 are two of its types [47].

As mentioned above that cancer cells put up several techniques to ensure faulty DNA repair system in the cell. The faulty DNA repair system now provides cancer cells with ability to produce more and more mutation. This higher rate of mutation gives the cancer cell advantage to manipulate cell machinery for uncontrolled growth. After choreographing the regulation of DNA repair system cancer then effects its fidelity, for the purpose it brings into the picture clustered mutation, which is a specific characteristic of cancer and cancer cells owe it to faulty DNA repair systems. An elaborate analysis of the clustered somatic mutations can identify error-prone DNA repair mechanism as a common source of mutations in active chromatin in human tumors [48].

#### **6. DNA repair and clustered mutation in cancer**

Clustered mutations, as the term suggest is localized hypermutation. There are three of its types namely- chromoplexy, chromothripsis, kataegis.

Chromoplexy refers to a class of complex DNA rearrangement observed in active regions of the genomes of cancer cell. The mechanism underlying complex rearrangements has not been established. But a proposed model says in the process DNA is brought together by the transcription factor working in a co regulated manner on different genes [49]. The process makes DNA in those places vulnerable to breakage and malfunctioning of DNA repair system make a jumbled-up repair of those broken pieces. Although this model has not been established but it's taken into account because chromoplexy is prevalent in only areas where there is active transcription and it can explain how DNA from multiple chromosomes may participate in a single chromoplexy event [50].

Chromothripsis is another such mutational process in which a number of chromosomal rearrangementsoccur in localized genomic regions in one or a few chromosomes together. The process takes place in a single event, where in the genomic space arise several double strand breaks. These breaks are then again joined by DNA repair system in a non-homologous manner. Once again, the crucial role of DNA repair system in the process of cancer survival and evolution is entrenched [51].

**199**

*Genomic Instability and DNA Repair in Cancer DOI: http://dx.doi.org/10.5772/intechopen.95736*

entire track of breakage [52].

high destabilizing potential [55].

accumulate mutation [53].

Kataegis mutational clusters are several hundred base pairs long, alternating between a long range of C → T and G → A substitutional pattern. This says it takes place in one of the two template strands during replication. It is more common than chromoplexy and chromothripsis. Kataegis hypothesis includes mismatch repair to activate and repair on locations of mismatch, making those regions single stranded and these single stranded regions are substrate to various modifying enzymes. These modifying enzymes then promote formation of mutation clusters along the

APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) enzymes and translesional DNA synthesizing enzyme are found to be associated with these events. There is literature available on this context. APOBEC enzymes are cytidine deaminase that is responsible for C → T transitions [53, 54]. H3K36me3 chromatin is normally protected from such somatic mutations, it is tri-methylation at the 36th lysine residue of the histone H3 protein, it relishes this protection from somatic mutation because of increased activity in canonical mismatch repair machinery at its locations. However, exposure to some carcinogens results in increased activity of a non-canonical, error-prone, mismatch repair pathway involving (POLH) DNA polymerase eta, which results in a relative increased mutation rate in H3K36me3-marked regions. This explains that some factors act as carcinogens not because they increase the mutation rate but because they relocate mutations to the more important regions of the genome. These environmental fac-

**7. Evidence of clustered mutation influencing repair pathways**

tors include alcohol, ionizing radiations, UV radiations etc. [6].

There are other evidence stating clustered mutations are driven by break induced replication (BIR) like mechanisms, which is associated with homologous recombination. Tremendous progress in whole genome analysis revealed that BIR is likely the mechanism of multiple genomic rearrangements in humans that give clustered mutation. To the date, there is no clear understanding of how BIR transforms from a beneficial pathway aimed at rescuing cells into a dangerous mechanism with

These events are very common to cancer cells. They serve as source for catastrophically higher rate of mutational events giving rise to sustainable amount of genomic instability. And as mentioned several times before genomic instability is the prime mechanism for the cancer cell to hold control over cellular machinery for uncontrolled division these events are very specific to cancer cells and a proper process of these events has not yet been elucidated [51]. But we can clearly see the potential role of DNA repair systems in these clustered mutational events. Through clustered mutations the cancer cell tries to exhaust DNA repair pathways. Repair pathways are meant to repair the DNA at a specific rate, and they are designed to tackle a limited burden. When mutation rate become overwhelming for them, their fidelity exhaust and that is the opportunity cancer cells create to

Cancer cells first changes the expression and regulation of the DNA repair systems by either epigenetic modifications, mutating its coding sequence or regulatory sequence. This in turn gives error prone DNA repair system for clustered mutation. Again, the clustered mutation also exhausts the DNA repair systems leaving no chance for fixing the genomic instability taking place in the cell. There still lies a debate on how these catastrophic mutational processes occur. But there is proof that

they are indebted to faulty repair systems for their birth [54].

*Genomic Instability and DNA Repair in Cancer DOI: http://dx.doi.org/10.5772/intechopen.95736*

*DNA - Damages and Repair Mechanisms*

MMR MLH1, MSH6,

MHS1

*DNA repair pathway genes affected in various ways in cancer.*

BRCA1/2, BRIP1

**DNA mutation (Germline)**

**DNA Repair Pathways**

Homologous Recombination

Direct Reversal DNA Damage

**Table 1.**

chromatin in human tumors [48].

chromoplexy event [50].

entrenched [51].

**6. DNA repair and clustered mutation in cancer**

three of its types namely- chromoplexy, chromothripsis, kataegis.

hook) code for a chromatin-associated protein that can modulate transcription by altering the chromatin architecture, HMGA1 and HMGA2 are two of its types [47]. As mentioned above that cancer cells put up several techniques to ensure faulty DNA repair system in the cell. The faulty DNA repair system now provides cancer cells with ability to produce more and more mutation. This higher rate of mutation gives the cancer cell advantage to manipulate cell machinery for uncontrolled growth. After choreographing the regulation of DNA repair system cancer then effects its fidelity, for the purpose it brings into the picture clustered mutation, which is a specific characteristic of cancer and cancer cells owe it to faulty DNA repair systems. An elaborate analysis of the clustered somatic mutations can identify error-prone DNA repair mechanism as a common source of mutations in active

NHEJ XRCC5 [43]

**DNA mutation (Somatic)**

BER *APE1,XRCC-1* MBD4, TDG [40, 41]

NER *ERCC1* XPC, RAD23A,

**Epigenetic Changes**

ERCC1

HMGA1

MSH3, MSH6

MGMT [44]

MSH2, MSH6 MLH1, MSH2,

BRCA1/2, PALB2 BRCA1, BRCA2,

**References**

[41, 42, 47]

[38, 39, 45]

[38, 39, 43]

Clustered mutations, as the term suggest is localized hypermutation. There are

Chromoplexy refers to a class of complex DNA rearrangement observed in active

regions of the genomes of cancer cell. The mechanism underlying complex rearrangements has not been established. But a proposed model says in the process DNA is brought together by the transcription factor working in a co regulated manner on different genes [49]. The process makes DNA in those places vulnerable to breakage and malfunctioning of DNA repair system make a jumbled-up repair of those broken pieces. Although this model has not been established but it's taken into account because chromoplexy is prevalent in only areas where there is active transcription and it can explain how DNA from multiple chromosomes may participate in a single

Chromothripsis is another such mutational process in which a number of chromosomal rearrangementsoccur in localized genomic regions in one or a few chromosomes together. The process takes place in a single event, where in the genomic space arise several double strand breaks. These breaks are then again joined by DNA repair system in a non-homologous manner. Once again, the crucial role of DNA repair system in the process of cancer survival and evolution is

**198**

Kataegis mutational clusters are several hundred base pairs long, alternating between a long range of C → T and G → A substitutional pattern. This says it takes place in one of the two template strands during replication. It is more common than chromoplexy and chromothripsis. Kataegis hypothesis includes mismatch repair to activate and repair on locations of mismatch, making those regions single stranded and these single stranded regions are substrate to various modifying enzymes. These modifying enzymes then promote formation of mutation clusters along the entire track of breakage [52].
