DNA repair of oxidative DNA damage in human carcinogenesis: Potential application for cancer risk assessment and prevention

Abstract

Efficient DNA repair mechanisms comprise a critical component in the protection against human cancer, as indicated by the high predisposition to cancer of individuals with germ-line mutations in DNA repair genes. This includes biallelic germ-line mutations in the MUTYH gene, encoding a DNA glycosylase that is involved in the repair of oxidative DNA damage, which strongly predispose humans to a rare hereditary form of colorectal cancer. Extensive research efforts including biochemical, enzymological and genetic studies in model organisms established that the oxidative DNA lesion 8-oxoguanine is mutagenic, and that several DNA repair mechanisms operate to prevent its potentially mutagenic and carcinogenic outcome. Epidemiological studies on the association with sporadic cancers of single nucleotide polymorphisms in genes such as OGG1, involved in the repair of 8-oxoguanine yielded conflicting results, and suggest a minor effect at best. A new approach based on the functional analysis of DNA repair enzymatic activity showed that reduced activity of 8-oxoguanine DNA glycosylase (OGG) is a risk factor in lung and head and neck cancer. Moreover, the combination of smoking and low OGG activity was associated with a higher risk, suggesting a potential strategy for risk assessment and prevention of lung cancer, as well as other types of cancer.

Low Integrated DNA Repair Score and Lung Cancer Risk

“…To measure such interindividual variations in DNA repair, we (13)(14)(15)(16)(17)(18) and others (19)(20)(21) took the approach of measuring the enzymatic activity of specific DNA repair enzymes, using peripheral blood mononuclear cell (PBMC) as the reporter tissue. Our primary focus was on DNA repair enzymes that target oxidative DNA damage, which has been implicated as a major factor in carcinogenesis (22).…”

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

“…9 DNA damage and DDR deficiencies are correlated with a wide range of diseases, including malignancies. 10,11 Three main components form the DDR machinery: DNA damage sensors, signal transducers and effectors. ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad3-related) are kinases that sense different forms of DNA breakage in order to trigger the DDR signaling cascade.…”

Biological activity assessment and phenolic compounds characterization from the fruit pericarp ofLitchi chinensisfor cosmetic applications

“…Overproduction and accumulation of free radicals, combined with deficiencies in enzymatic and non-enzymatic self-defense antioxidants, negatively affect biological systems (Wickens, 2001). Cellular oxidative damage is encountered in many diseases, including cancer (Paz-Elizur et al, 2008), Alzheimer's (Moreira et al, 2005), aging (Wickens, 2001), inflammation (Beal, 2003), diabetes (Naito et al, 2006), Parkinson's (Beal, 2003) and AIDS (Sepulveda & Watson, 2002). Therefore, antioxidants are important for preventing the negative effects of radicals.…”