title: DNA repair and cell cycle checkpoint defects as drivers and therapeutic targets in melanoma.
abstract: The ultraviolet radiation (UVR) component of sunlight is the major environmental risk factor for melanoma, producing DNA lesions that can be mutagenic if not repaired. The high level of mutations in melanomas that have the signature of UVR-induced damage indicates that the normal mechanisms that detect and repair this damage must be defective in this system. With the exception of melanoma-prone heritable syndromes which have mutations of repair genes, there is little evidence for somatic mutation of known repair genes. Cell cycle checkpoint controls are tightly associated with repair mechanisms, arresting cells to allow for repair before continuing through the cell cycle. Checkpoint signaling components also regulate the repair mechanisms. Defects in checkpoint mechanisms have been identified in melanomas and are likely to be responsible for increased mutation load in melanoma. Loss of the checkpoint responses may also provide an opportunity to target melanomas using a synthetic lethal approach to identify and inhibit mechanisms that compensate for the defective checkpoints.
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Qld, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pavey
authors.forename: Loredana
authors.initials: L
authors.lastname: Spoerri
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
mesh_terms: D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D006801:Humans; D008545:Melanoma / Q000473:pathology* / Q000628:therapy*; D058990:Molecular Targeted Therapy; D014466:Ultraviolet Rays
keywords: DNA damage; DNA repair; UV; cell cycle checkpoint