Error-prone translesion replication of damaged DNA suppresses skin carcinogenesis by controlling inflammatory hyperplasia.
The induction of skin cancer involves both mutagenic and proliferative responses of the epidermis to ultraviolet (UV) light. It is believed that tumor initiation requires the mutagenic replication of damaged DNA by translesion synthesis (TLS) pathways. The mechanistic basis for the induction of proliferation, providing tumor promotion, is poorly understood. Here, we have investigated the role of TLS in the initiation and promotion of skin carcinogenesis, using a sensitive nucleotide excision repair-deficient mouse model that carries a hypomorphic allele of the error-prone TLS gene Rev1. Despite a defect in UV-induced mutagenesis, skin carcinogenesis was accelerated in these mice. This paradoxical phenotype was caused by the induction of inflammatory hyperplasia of the mutant skin that provides strong tumor promotion. The induction of hyperplasia was associated with mild and transient replicational stress of the UV-damaged genome, triggering DNA damage signaling and senescence. The concomitant expression of Interleukin-6 (IL-6) is in agreement with an executive role for IL-6 and possibly other cytokines in the autocrine induction of senescence and the paracrine induction of inflammatory hyperplasia. In conclusion, error-prone TLS suppresses tumor-promoting activities of UV light, thereby controlling skin carcinogenesis.
Tsaalbi-Shtylik
Anastasia
A
Department of Toxicogenetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Verspuy
Johan W A
JW
Jansen
Jacob G
JG
Rebel
Heggert
H
Carlée
Leone M
LM
van der Valk
Martin A
MA
Jonkers
Jos
J
de Gruijl
Frank R
FR
de Wind
Niels
N
D000483:Alleles; D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics; D014466:Ultraviolet Rays
D015850:Interleukin-6