Crosslinking of DNA
Encyclopedia
Crosslinks in DNA
occur when various exogenous or endogenous agents react with two different positions in the DNA. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein
. DNA replication
is blocked by crosslinks, which causes replication arrest and cell death if the crosslink is not repaired
.
The RAD51
family plays a role in repair.
such as 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU, Carmustine
)) and nitrogen mustard
which are used in chemotherapy
can cross link with DNA at N7 position of guanine
on the opposite strands forming interstrand crosslink.
Cisplatin
(cis-diamminedichloroplatinum(II)) and its derivative forms DNA cross links as monoadduct, interstrand crosslink, intrastrand crosslink or DNA protein crosslink. Mostly it acts on the adjacent N-7 guanine forming 1, 2 intrastrand crosslink.
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
occur when various exogenous or endogenous agents react with two different positions in the DNA. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
is blocked by crosslinks, which causes replication arrest and cell death if the crosslink is not repaired
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
.
The RAD51
RAD51
RAD51 is a human gene. The protein encoded by this gene is a member of the RAD51 protein family which assist in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA and yeast Rad51...
family plays a role in repair.
I. Exogenous Cross Linking Agents
Alkylating agentsAlkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....
such as 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU, Carmustine
Carmustine
Carmustine or BCNU is a mustard gas-related β-chloro-nitrosourea compound used as an alkylating agent in chemotherapy...
)) and nitrogen mustard
Nitrogen mustard
The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, in principle these compounds can also be deployed as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by...
which are used in chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
can cross link with DNA at N7 position of guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
on the opposite strands forming interstrand crosslink.
Cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
(cis-diamminedichloroplatinum(II)) and its derivative forms DNA cross links as monoadduct, interstrand crosslink, intrastrand crosslink or DNA protein crosslink. Mostly it acts on the adjacent N-7 guanine forming 1, 2 intrastrand crosslink.
II. Endogenous Cross Linking Agents
- Nitrous acidNitrous acidNitrous acid is a weak and monobasic acid known only in solution and in the form of nitrite salts.Nitrous acid is used to make diazides from amines; this occurs by nucleophilic attack of the amine onto the nitrite, reprotonation by the surrounding solvent, and double-elimination of water...
is formed in the stomach from dietary sources of nitrites. It induces formation of interstrand DNA crosslinks at the aminogroup of exocyclic N2 of guanine at CG sequences.
- Reactive chemicals such as malondialdehydeMalondialdehydeMalondialdehyde is the organic compound with the formula CH22. The structure of this species is more complex than this formula suggests. This reactive species occurs naturally and is a marker for oxidative stress.- Structure and synthesis :...
which are formed endogenously as the product of lipid peroxidationLipid peroxidationLipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...
. They create etheno adducts formed by aldehydeAldehydeAn aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
which undergo rearrangements to form crosslinks on opposite strands.
- PsoralenPsoralenPsoralen is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone...
s are natural compounds (furocoumarins) present in plants. These compounds get activated in the presence of UV - A. They form covalent adducts with pyrimidines. Covalent adducts are formed by linking 3, 4 (pyronePyronePyrones or pyranones are a class of cyclic chemical compounds. They contain an unsaturated six membered ring containing one oxygen atom and a ketone functional group. There are two isomers denoted as 2-pyrone and 4-pyrone. The 2-pyrone structure is found in nature as part of the coumarin ring...
) or 4', 5’ (furanFuranFuran is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen. The class of compounds containing such rings are also referred to as furans....
) edge of psoralen to 5, 6 double bond of thymineThymineThymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
. Psoralens can form two types of monoadducts and one diadduct (an interstrand crosslink) reacting with thymineThymineThymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
. The crosslinking reaction by Psoralens targets TA sequences intercalating in DNA and linking one base of the DNA with the one below it. Psoralen adducts cause replication arrest and is used in the treatment of psoriasisPsoriasisPsoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
and vitiligoVitiligoVitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
.
- AldehydeAldehydeAn aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
s such as acroleinAcroleinAcrolein is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity...
and crotonaldehydeCrotonaldehydeCrotonaldehyde is a chemical compound with the formula CH3CH=CHCHO. The compound is usually sold as a mixture of the E- and Z-isomers, which differ with respect to the relative position of the methyl and formyl groups. The E-isomer is more common...
found in tobacco smoke or automotive exhaust can form DNA interstrand crosslinks in DNA. Guanine adducts of DNA can also react with protein. A Schiff baseSchiff baseA Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
formation between protein and aldehyde causes this DNA protein interstrand link
- FormaldehydeFormaldehydeFormaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...
(HCHO) induces protein-DNA and protein-protein crosslinks, and is a common reagent of choice for molecular biology experiments. These crosslinks may be reversed by incubation at 70°C.
External links
- Interactive structure for cisplatin and DNA adduct formation - Interactive structure for psoralen and crosslinked DNA- Psoralen Ultraviolet A Light Treatment http://www.um-jmh.org/body.cfm?id=1545