# Indirect DNA damage

File:Indirect DNA damage.png
Indirect DNA damage: The chromophore absorbs UV-light ( * denotes an excited state), and the energy of the excited state is creating singlet oxygen (1O2) or a hydroxyl radical (•OH) which then in turn damages (oxidizes) the DNA.

The distinction between direct DNA damage and indirect DNA damage is highly relevant for the discussion of UV-induced skin damage, the effects of sunscreens, and the mechanism of photocarcinogenesis (formation of e.g. Melanoma).

Indirect DNA damage occurs when a UV-photon is absorbed in the human skin by a chromophore that does not have the ability to convert the energy into harmless heat very quickly. Molecules which do not have this ability have a long lived excited state. This long lifetime leads to a high probability for reactions with other molecules - so called bimolecular reactions. Melanin and DNA have extremely short lifetimes in the range of a few femtoseconds (10-15s) [1] but the active ingredients of sunscreens do not efficiently dissipate the energy of the UV-photon as heat (see photoprotection). The excited state lifetime of these substances is 1000 to 1000000 times longer than the lifetime of melanin[2] and therefore they may cause damage to living cells which come into contact with them.[3][4][5][6]

The molecule which originally absorbs the UV-photon is called a "chromophore". The bimolecular reactions can either occur between the excited chromophore and DNA, or between the excited chromophore and another species to produce free radicals and Reactive Oxygen Species. These reactive chemical species can reach DNA by diffusion and the bimolecular reaction will damage the DNA (oxidative stress). Importantly, indirect DNA damage does not result in any warning signal or pain in the human body.

The mutations which result from direct DNA damage and those which result from indirect DNA damage are different, and genetic analysis of melanomas can elucidate which DNA damage has caused each respective skin cancer. Studies using these techniques have found that 92% of melanomas caused by a mutation in the BRAF gene are caused by indirect DNA damage. Mutations in the BRAF gene were found in 59% of the analyzed melanomas. [7]

The bimolecular reactions that cause the indirect DNA damage are illustrated in the figure:

${\displaystyle \mathrm {(Chromophore)^{*}+{}^{3}O_{2}\ {\xrightarrow {}}\ Chromophore+{}^{1}O_{2}} }$

1O2 is reactive harmful singlet oxygen:

${\displaystyle \mathrm {{}^{1}O_{2}+intact\ DNA\ {\xrightarrow {}}\ {}^{3}O_{2}+damaged\ DNA} }$

## Consequences of indirect DNA damage

There are three types of skin cancer: basal-cell carcinoma, squamous cell carcinoma and the malignant melanoma. Malignant melanoma is rare, but it is responsible for 75% of all skin cancer related deaths. While the less relevant forms (basal-cell carcinoma and squamous cell carcinoma) are caused by the direct DNA damage, the number one cause of skin cancer related deaths is mostly a result of indirect DNA damage. For this reason, indirect DNA damage stemming from free radicals and reactive oxygen species (ROS) is arguably much more relevant for the public health than direct DNA damage.

## Location of the damage

Direct DNA damage is confined to areas that can be reached by UV-B light. In contrast free radicals can travel through the body and affect other areas - possibly even inner organs. The traveling nature of the indirect DNA damage can be seen in the fact that the malignant melanoma can occur in places that are not directly illuminated by the sun - this is in contrast to basal-cell carcinoma and squamous cell carcinoma which only appear on directly illuminated locations of the body.

## Effects of topical vs. absorbed sunscreen

Indirect DNA damage is reduced by the topical sunscreen that stays on the surface of the skin. However, if sunscreen penetrates the epidermal barrier and gets into contact with living tissue, the indirect DNA damage is amplyfied manyfold which causes damage to living tissue even at very low concentrations (10 μmol/L).[5][6][3][4] This is due to the inferior photoprotective properties of sunscreen molecules compared with melanin and DNA.

7. Davies H.; Bignell G. R.; Cox C.; (2002). "Mutations of the BRAF gene in human cancer". Nature. 417: 949–954. Unknown parameter |month= ignored (help)