Chemical excitation of electrons: A dark path to melanoma
Open accessAbstract
Sunlight's ultraviolet wavelengths induce cyclobutane pyrimidine dimers (CPDs), which then cause mutations that lead to melanoma or to cancers of skin keratinocytes. In pigmented melanocytes, we found that CPDs arise both instantaneously and for hours after UV exposure ends. Remarkably, the CPDs arising in the dark originate by a novel pathway that resembles bioluminescence but does not end in light: First, UV activates the enzymes nitric oxide synthase (NOS) and NADPH oxidase (NOX), which generate the radicals nitric oxide (NO) and superoxide (O2(-)); these combine to form the powerful oxidant peroxynitrite (ONOO(-)). A fragment of the skin pigment melanin is then oxidized, exciting an electron to an energy level so high that it is rarely seen in biology. This process of chemically exciting electrons, termed "chemiexcitation", is used by fireflies to generate light but it had never been seen in mammalian cells. In melanocytes, the energy transfers radiationlessly to DNA, inducing CPDs. Chemiexcitation is a new source of genome instability, and it calls attention to endogenous mechanisms of genome maintenance that prevent electronic excitation or dissipate the energy of excited states. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin.
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In mammals, chemiexcitation was discovered as direct energy transfer from excited melanin to DNA, producing the lethal and carcinogenic cyclobutane pyrimidine dimer.
“In mammals, chemiexcitation was discovered as energy transferred directly from excited melanin to DNA, creating the lethal and carcinogenic cyclobutane pyrimidine dimer.”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [33]
The Abstract says energy from chemically excited melanin transfers to DNA and induces CPDs; the Introduction (§1) describes CPDs as lethal and mutagenic. But §4 says the final transfer steps have not been demonstrated directly and the mechanism is unknown, so the claim overstates how firmly direct transfer was established. Page numbers were not supplied. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn the first step of that reaction, brief UV exposure activates NOS and NOX to generate nitric oxide and superoxide for hours afterward; the induction mechanism is unknown.
“a brief UV exposure activates the enzymes nitric oxide synthase (NOS) and NADPH oxidase (NOX) to generate the radicals nitric oxide (•NO) and superoxide (O2•−) for hours afterward; the mechanism of induction is still not known.”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [33]
The Abstract describes UV activation of NOS and NOX and their generation of nitric oxide and superoxide. Section 4 says the enzymes are UV-inducible within minutes, while Section 5 describes prolonged UV induction that helps account for delayed CPD formation. Our copy does not state that the mechanism of enzyme induction is unknown. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe melanin-to-DNA chemiexcitation process is initiated by nitric oxide and superoxide, radicals triggered by ultraviolet light or inflammation.
“That process was initiated by nitric oxide and superoxide, radicals triggered by ultraviolet light or inflammation.”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [33]
The Abstract and §4 (page unavailable) describe UV activating enzymes that generate nitric oxide and superoxide; the radicals combine to form peroxynitrite, which initiates the melanin-to-DNA chemiexcitation pathway. Our copy does not say that inflammation triggers those radicals, so that part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe excited carbonyl transfers its energy to nearby DNA without photons, producing the lethal and mutagenic CPD.
“with the excited carbonyl transferring its energy to nearby DNA, without photons, to make the lethal and mutagenic cyclobutane pyrimidine dimer”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [33]
Section 4, “CPDs from chemiexcitation” (page not provided), describes photon-independent energy transfer from an excited carbonyl to DNA as a proposed route to CPDs. It explicitly says the final steps have not been demonstrated directly, so the claim presents the mechanism more definitively than the source does. The Introduction identifies CPDs as lethal and mutagenic. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe chemiexcitation events were discovered in melanocyte cell cultures and murine skin using a fluorescent triplet-state reporter, blocking with vitamin E or sorbate, and identifying dCPDs by mass spectrometry and immunohistochemistry.
“The chemiexcitation events were discovered in melanocyte cell cultures and in murine skin, using a fluorescent triplet-state reporter to detect the transient triplet state, blocking these events with the radical scavenger vitamin E or the triplet-specific quencher sorbate, and identifying dCPDs using mass spectrometry and immunohistochemistry.”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [33]
Section 2, “CPDs in the dark” (page unavailable), describes delayed CPDs in cultured melanocytes and mouse epidermis and identifies CPDs by mass spectrometry. Section 4, “CPDs from chemiexcitation” (page unavailable), describes the DBAS fluorescent triplet-state reporter and prevention of delayed CPDs by vitamin E or ethyl sorbate. Our copy describes an anti-CPD antibody ELISA, but the passages found do not establish the claimed use of immunohistochemistry. (LLM, conf=0.86)
Experimental — accuracy not yet measured
The authors' laboratory discovered that chemiexciting melanin sends melanocytes toward melanoma even in the dark.
“Recently our laboratory discovered that chemiexciting the skin pigment melanin sends melanocytes down the path to melanoma even in the dark”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [33]
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References 62 · Cited by 47
Research works printed but not linked: 2
- [34]Wilson T Hastings JW Bioluminescence: Living Lights, Lights for Living Cambridge, MA 2013
- [60]Lamola AA Fundamental aspects of the spectroscopy and photochemistry of organic compounds; electronic energy transfer in biologic systems; and photosensitization Pathak MA Harber LC Seiji M Kukita A Sunlight and Man University of Tokyo Press Tokyo 1972 17 55
- Authors
- Premi, S., & Brash, D. E.
- Affiliations
- Yale University (US)
- Yale Cancer Center (US)
- Corresponding author
- Brash, Douglas E.
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 44
- Pages
- 169-177
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- PMC
- PMC4958542
- OpenAlex
- W2418708337
- Cited by
- 47
- References
- 62
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 1 · 2019: 4 · 2018: 6 · 2017: 3
- FWCI
- 0.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- L'Oreal, Inc (5P50CA12197409)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- melanoma, ultraviolet radiation, cyclobutane pyrimidine dimers, chemiexcitation, melanocytes, nitric oxide, superoxide, peroxynitrite, NADPH oxidase, nitric oxide synthase, genomic instability, DNA damage, radiation-induced mutations
- MeSH terms
- DNA Damage, Electrons, Humans, Melanins, Melanoma, Neoplasms, Radiation-Induced, Nitric Oxide, Pyrimidine Dimers, Skin, Skin Neoplasms, Sunlight, Superoxides, Ultraviolet Rays, Keratinocytes, Nitric Oxide Synthase, NADPH Oxidases, Peroxynitrous Acid
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