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.

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