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DNA-protein crosslinking can be caused by a variety of chemical and physical agents, including transition metals, ionizing radiation, and endogenous aldehydes, in addition to chemotherapeutic agents. [26] Similar to DNA crosslinking, DNA-protein crosslinks are lesions in cells that are frequently damaged by UV radiation.
Some alkylating agents are active under conditions present in cells; and the same mechanism that makes them toxic allows them to be used as anti-cancer drugs. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate.
Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF. [23] [24] Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA ...
Mostly they act on the adjacent N-7 position of guanine, forming a 1, 2 intrastrand crosslink. [4] [5] The resultant crosslinking inhibits DNA repair and/or DNA synthesis. This mechanism leads to specific patterns of damage in DNA, which can kill cancer cells but can also increase the risk of secondary tumors developing. [6]
The main mechanism of cancer development involves increased exposure to acetaldehyde, a carcinogen and breakdown product of ethanol. [41] Acetaldehyde induces DNA interstrand crosslinks, a form of DNA damage. These can be repaired by an inaccurate replication-coupled DNA repair pathway. [42]
2072 50505 Ensembl ENSG00000175595 ENSMUSG00000022545 UniProt Q92889 Q9QZD4 RefSeq (mRNA) NM_005236 NM_015769 RefSeq (protein) NP_005227 NP_056584 Location (UCSC) Chr 16: 13.92 – 13.95 Mb Chr 16: 12.93 – 12.97 Mb PubMed search Wikidata View/Edit Human View/Edit Mouse ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ...
This ability to bind covalently to DNA via their alkyl group is the primary cause for their anti-cancer effects. [37] DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink).
HN1 (bis(2-chloroethyl)ethylamine), a DNA crosslinker. Like most crosslinkers, this molecule has two reactive groups. Intrastrand DNA crosslinks have strong effects on organisms because these lesions interfere with transcription and replication. These effects can be put to good use (addressing cancer) or they can be lethal to the host organism.