Target intelligence / Profile preview

DNA crosslinking and alkylation sites (None)

Target
None
Molecular classification
Other, DNA damage site
01

Overview

DNA crosslinking and alkylation sites refer to chemical modifications of DNA, resulting from the covalent attachment of alkyl groups or crosslinking between DNA strands, or between DNA and proteins. These lesions are primarily formed by the action of chemotherapeutic agents such as alkylating agents or platinum-based drugs, which attack nucleophilic sites on DNA bases (especially guanine), leading to the formation of intra- or inter-strand crosslinks and monoadducts. Such lesions disrupt DNA replication and transcription, causing cell cycle arrest and eventually cell death. The induction of DNA crosslinking/alkylation is exploited therapeutically to kill rapidly dividing cancer cells, but also poses a risk to normal cells, leading to genotoxic side effects and elevated risk of secondary cancers. These sites are not molecular "targets" per se, but are the direct result of damage caused by pharmacological or environmental agents.

Other names
DNA crosslink site(s)DNA alkylation site(s)DNA adducts (context-dependent)DNA lesions (context-dependent)
02

Mechanism of action

Covalent alkylation or crosslinking of DNA nucleotides, forming intra- or inter-strand links that prevent DNA unwinding, replication, and transcription, ultimately leading to cell cycle arrest and death

03

Biological functions

Cell death (through apoptosis or necrosis)Inhibition of DNA replication and transcriptionImpaired cell divisionCellular response to DNA damage
04

Disease associations

Cancer (as chemotherapeutic target/process)Other (since DNA damage can also contribute to aging, mutagenesis, and diseases linked to genome instability)
05

Safety considerations

Off-target DNA damage leading to mutagenesis and secondary malignanciesGeneral cytotoxicity in non-cancerous proliferating cells (bone marrow, gut epithelium, etc.)Therapy-induced secondary cancerInfertility and organ damage from cumulative normal tissue exposure
06

Interacting drugs

Nitrogen mustard analogs (e.g., cyclophosphamide, melphalan, chlorambucil)

3 more in the full profile.

07

Biomarkers

DNA adduct quantification (e.g., mass spectrometry-based detection of crosslinks/adducts)γ-H2AX (marker of DNA double-strand breaks)Cellular markers of DNA damage response (e.g., increased p53, cell cycle arrest)

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