Genomic Instability and DNA Repair in Cancer

*Bhaswatee Das, Bipasha Choudhury, Aditya Kumar and Vishwa Jyoti Baruah*

## **Abstract**

Mutations in genome are essential for evolution but if the frequency of mutation increases it can evince to be detrimental, for a steady maintenance there exist a detailed complex system of surveillance and repair of DNA defects. Therefore, fault in DNA repair processes raises the probability of genomic instability and cancer in organisms. Genome instability encompasses various aspects of mutations from indels to various somatic variants. The chapter tries to present an overview of how cancer puts up several ways to ensure suppression of the fidelity in our DNA repair system. Cancer cells assure failure of efficient DNA repair mechanisms by innumerous ways, by mutation and epigenetic modifications in repair genes themselves or genes controlling their expression and functions, other by some catastrophic events like kataegis, chromothripsis and chromoplexy. These are clustered mutations taking place at a particular genomic locus which deluge the repair process. Cancer generation and evolution is dependent largely on genome instability, so it applies many strategies to overcome one of its basic obstacles that is DNA repair, targeting these DNA repair genes has also demonstrated to be helpful in cancer therapy; but an intricate understanding of recalcitrant process and mechanisms of drug resistant in cancer will further enhance the potential in them.

**Keywords:** genome instability, DNA repair, cancer, epigenetic modifications, clustered mutation

### **1. Introduction**

Genome is the basis of life of an organism and mutation in genome is essential for adaptation [1]. A mutation is a change in genomic sequence, they are the result of mistakes a cell makes while copying a piece of genome during replication or sometimes mutation is influenced by exogenous agents. Mutations have the capacity to influence gene expression depending on their location in the genome, gene structure and intergenic region. They possess this power to affect with such consequences because mutation in coding region of the genome might give rise to a truncated protein with no use or might compromise its fidelity. Alternatively, it can also endow the protein with some advantages with its function. Their presence in the regulatory region may increase or decrease its expression. This change in level of expression also affects cellular mechanisms since proteins are required by the cell in specific amounts. Therefore, these changes give either an advantage or a disadvantage depending on the effect it may produce but with a higher rate of mutation cell loses

its capacity to maintain genome integrity, that give rise to genome instability, it is a range of DNA alterations which irreversibly change information content of the genome. To keep a check on all such mutational process cell has an elaborated system of DNA repair and checkpoints [2, 3].

In unicellular organisms, a delicate balance exists between maintenance of genome stability and the tolerance to genome instability. They have harnessed this instability to mediate phase and antigenic variation that instead imparts them advantage for survival [4]. But any catastrophic changes in the genome are detrimental to them, in simple words genome instability for unicellular organisms is deleterious if it becomes impossible for them to take a control on it. For complex multicellular organisms like humans, we accumulate DNA damage over years that lead to genome instability and this genome instability is one such reason for aging [5]. A lot of studies are available that clearly state that the genome instability is a hallmark of aging and cancer. Cancer as we all know is a disease where the cell's own regulatory system goes wrong and there is uncontrolled division and to relief itself from cell cycle checkpoints and escape immune surveillance and apoptosis a cell must accumulate enough mutations. Cancer usually arises from benign tumor; these are localized abnormal growth of cells that cannot spread to other parts of the body. They undergo some more mutations and turn malignant now they have the capability to spread. Although there are certain types that do not form benign tumors such as leukemias, lymphomas and myelomas because of their nature [6].

There are several ways by which cell resist accumulation of DNA damage such as scavenging DNA damaging molecules, repairing erroneous DNA and at last if the cell is damaged beyond repair then apoptosis [7]. Despite all these measures the cell sometimes gathers enough mutation for the genome to be unstable and it to be cancerous [8]. Reasons behind DNA damage can be endogenous or exogenous. These damages are first perceived by the cell and a process of DNA repair is triggered on. Any discrepancies in the process of DNA repair predispose the cell to malignant transformation. Therefore, detection and repair of changes in the genome is prime to maintain cellular integrity. From this we can very well understand the importance of the role by DNA repair mechanism on maintaining genome integrity [9].

Its role can also be understood in hereditary cancers where most of the time one allele of a gene involved in one of the repair systems remains mutated at birth and the other turns mutated in course of time and the cancer arises. There are other example like the famous Breast Cancer genes; namely BRCA1 and BRCA2 where mutation in any one of them predisposes to breast and ovarian cancer. About 5–10% of people having mutation in BRCA genes encountered cancer once, mutation in these genes also predisposes the individual to cancer recurrence. We all know mutations owe their effectiveness to their space, therefore not all mutation in these genes is potentially effective in predisposing the person to cancer. Several mutations are identified till date and categorized by its influence. Both the genes BRCA1 and BRCA2 are involved in transcriptional regulation in response to DNA damage, most of these functions are mediated by the cellular proteins that interact with them [10]. BRCA1/2 is a tumor-suppressor and gets recruited in DNA damage loci, it has many other functions like damage induced cell cycle checkpoints activation, its association with homologous recombination as well as non-homologous recombination has also been established [11]. The exact mechanism behind BRCA controlling all these processes is still unclear but there is evidence of its direct association [10]. There is a specific type of drug available acting on these cells with mutation in BRCA genes; poly ADP-ribose polymerase (PARP) inhibitors. Their effect is specific to the cancer cells as they are usually deficit in homologous recombination, we will discuss this later in the chapter [11]*.* Current chapter gives a description on mutations and epigenetic modifications of the DNA repair genes which aid genomic instability in cancer.

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**Figure 1.**

*Genomic instability influencing cancer.*

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

**2. An introduction to genome instability in cancer**

Genomic instability refers to chromosomal changes, ploidy change or changes in nucleic acid sequence. In multicellular organisms, genome instability is fundamental to carcinogenesis [12]. Genome instability in cancer is associated with the ploidy change, chromosomal translocations, inversions, insertion, deletions, DNA breaks or any abnormal changes in DNA tertiary structure that can cause DNA damage, or the misexpression of genes (**Figure 1**). Ploidy change is accumulation of extra copies of chromosome(s) or parts of chromosome. Chromosomal translocations are phenomenon when a part of the chromosome breaks and get attached to some other chromosome. Inversions are breakage of a piece of DNA and getting attached to the same position in an inverted orientation. It happens when the DNA undergoes breakage and rearrangement. Insertion as the name suggests is the insertion of nucleotides on a locus in the genome. In deletions, there is deletion of nucleotide from specific loci in the genome. DNA breaks are either double stranded or single stranded depending, single stranded are easily repaired because here template is readily available but there are specific repair pathways dedicated to double stranded breaks since template is lost and the repair pathways has to bring it from the other pair and in some cases, there is error prone repair [8, 13]. Microsatellite instability is another such phenomenon influencing genomic instability. Genome instability fuels the cancer cells with changes that help it to evolve and escape death. Additionally, it also plays a critical role in cancer initiation and progression by overcoming immune surveillance, attaining uncontrolled cell division, more DNA damage, etc. [14] In normal cells, genome is protected at every stage of the cell cycle, every step from DNA replication to chromosome packaging. Every step is very precisely monitored for faults. Several processes are involved in this such as cell cycle checkpoints, DNA damage checkpoints and DNA repair. When a normal cell turns cancerous, these fault monitoring systems are manipulated; presence of genomic instability itself indicates the failure of one or many of these safety nets (**Figure 1**) [13]. Interpreting the underlying mechanisms for imbalance in genome integrity would yield new avenues for precision therapies and clinical decision-making. Lot of research has been centered to genome instability to understand it and hold control over its initiation and progress in a hope to conquer cancer, which is the world

*DNA - Damages and Repair Mechanisms*

of DNA repair and checkpoints [2, 3].

its capacity to maintain genome integrity, that give rise to genome instability, it is a range of DNA alterations which irreversibly change information content of the genome. To keep a check on all such mutational process cell has an elaborated system

In unicellular organisms, a delicate balance exists between maintenance of genome stability and the tolerance to genome instability. They have harnessed this instability to mediate phase and antigenic variation that instead imparts them advantage for survival [4]. But any catastrophic changes in the genome are detrimental to them, in simple words genome instability for unicellular organisms is deleterious if it becomes impossible for them to take a control on it. For complex multicellular organisms like humans, we accumulate DNA damage over years that lead to genome instability and this genome instability is one such reason for aging [5]. A lot of studies are available that clearly state that the genome instability is a hallmark of aging and cancer. Cancer as we all know is a disease where the cell's own regulatory system goes wrong and there is uncontrolled division and to relief itself from cell cycle checkpoints and escape immune surveillance and apoptosis a cell must accumulate enough mutations. Cancer usually arises from benign tumor; these are localized abnormal growth of cells that cannot spread to other parts of the body. They undergo some more mutations and turn malignant now they have the capability to spread. Although there are certain types that do not form benign tumors such as leukemias, lymphomas and myelomas because of their nature [6]. There are several ways by which cell resist accumulation of DNA damage such as scavenging DNA damaging molecules, repairing erroneous DNA and at last if the cell is damaged beyond repair then apoptosis [7]. Despite all these measures the cell sometimes gathers enough mutation for the genome to be unstable and it to be cancerous [8]. Reasons behind DNA damage can be endogenous or exogenous. These damages are first perceived by the cell and a process of DNA repair is triggered on. Any discrepancies in the process of DNA repair predispose the cell to malignant transformation. Therefore, detection and repair of changes in the genome is prime to maintain cellular integrity. From this we can very well understand the importance of the role by DNA repair mechanism on maintaining genome integrity [9]. Its role can also be understood in hereditary cancers where most of the time one allele of a gene involved in one of the repair systems remains mutated at birth and the other turns mutated in course of time and the cancer arises. There are other example like the famous Breast Cancer genes; namely BRCA1 and BRCA2 where mutation in any one of them predisposes to breast and ovarian cancer. About 5–10% of people having mutation in BRCA genes encountered cancer once, mutation in these genes also predisposes the individual to cancer recurrence. We all know mutations owe their effectiveness to their space, therefore not all mutation in these genes is potentially effective in predisposing the person to cancer. Several mutations are identified till date and categorized by its influence. Both the genes BRCA1 and BRCA2 are involved in transcriptional regulation in response to DNA damage, most of these functions are mediated by the cellular proteins that interact with them [10]. BRCA1/2 is a tumor-suppressor and gets recruited in DNA damage loci, it has many other functions like damage induced cell cycle checkpoints activation, its association with homologous recombination as well as non-homologous recombination has also been established [11]. The exact mechanism behind BRCA controlling all these processes is still unclear but there is evidence of its direct association [10]. There is a specific type of drug available acting on these cells with mutation in BRCA genes; poly ADP-ribose polymerase (PARP) inhibitors. Their effect is specific to the cancer cells as they are usually deficit in homologous recombination, we will discuss this later in the chapter [11]*.* Current chapter gives a description on mutations and epigenetic modifications

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of the DNA repair genes which aid genomic instability in cancer.
