Maintenance of genomic stability and cancer

Cancer is a genetic disease of the somatic cells. Its initiation and development are caused by accumulating genomic alterations, ranging from point mutations to gross chromosomal aberrations. Maintenance of genomic stability and integrity is thus essential for prevention of neoplasia (1,2). DNA damage is arguably the greatest threat to genome stability. DNA-damaging agents induce a plethora of DNA lesions that can be cytotoxic and/or mutagenic, with consequences ranging from malfunction of the cell, to cell death or malignant transformation (3,4). Many DNA-damaging agents are therefore potent carcinogens (5–7).

The cellular defense system against this threat is the DNA damage response (DDR) – an elaborate signaling network activated by DNA damage that swiftly modulates many physiological processes (4,8–12). It is not surprising that various players in the DDR are tumor suppressors; germline mutations in damage response genes lead to inherited predisposition to cancer (13–20) or to complex genomic instability syndromes characterized by a predisposition to develop cancer (21–25). Functional dissection of the DDR is therefore expected to identify additional players in cancer formation. The DDR is also highly relevant to cancer treatment, as radiotherapy and many chemotherapeutic drugs are DNA-damaging agents. Understanding the DDR is thus crucial to design of better treatment regimens, minimization of side effects, identification of new targets for drug therapy, discovery of new methods for radiosensitization and chemosensitization of tumor cells, and resolution of the major problem of radio- and drug-resistance.