Diverse DNA Damage Response Mechanisms in Cancer: From Tumor Suppression to Therapeutic Targets

摘要

Cellular DNA damage response (DDR) mechanisms exist to protect against genomic instability and phenotypes such as aging and cancer. Sources of DNA damage include metabolic by-products like reactive oxygen species and estrogen and cholesterol metabolites, as well as environmental exposure to ultraviolet light. Also, spontaneous hydrolysis reactions can create abasic sites and deamination.1 Molecular DDR networks first sense or recognize the damage, and then transduce signals to appropriate effector molecules. Possible outcomes for an executed response can include cell cycle arrest, DNA repair, and apoptosis, depending on the severity of the damage. Adult stem cells can also activate terminal differentiation in response to DNA damage.2 Incorrectly repaired or unrepaired DNA, if allowed to persist, can result in DNA "scars" that can foster further mutations, chromosomal aberrations, cellular transformation and cancer development.3 Somewhat paradoxically, cancer cells with DDR defects can have enhanced resistance or sensitivity to DNA-damaging ionizing radiation or cytotoxic drugs, depending on the particular defect.