DNA alkylation repair

Definition

Target type: biologicalprocess

The repair of alkylation damage in DNA, e.g. the removal of a non-physiological alkyl group from a nucleobase. This is usually mediated by DNA alkyltransferases. [PMID:10946226, PMID:35543797]

DNA alkylation repair is a cellular process that removes alkyl groups from DNA, which are damaging modifications that can lead to mutations and cancer. Alkylation occurs when an alkyl group (e.g., methyl, ethyl, or propyl) is added to a base in DNA, typically at the N7 position of guanine or the O6 position of guanine. These modifications disrupt the normal base pairing of DNA, leading to errors in replication and transcription. The repair of alkylated DNA involves two main pathways: direct reversal and base excision repair (BER).

Direct reversal involves the removal of the alkyl group directly from the damaged base, without removing the base itself. This is accomplished by enzymes called alkyltransferases, which transfer the alkyl group to a cysteine residue on their own protein. The most well-studied alkyltransferase is O6-methylguanine-DNA methyltransferase (MGMT), which removes methyl groups from the O6 position of guanine.

BER is a more complex pathway that involves multiple enzymes and is responsible for removing a wide range of damaged bases, including alkylated bases. In BER, the damaged base is first recognized and removed by a DNA glycosylase enzyme. This leaves an apurinic/apyrimidinic (AP) site in the DNA backbone. The AP site is then cleaved by an AP endonuclease, creating a single-strand break. The gap is then filled by a DNA polymerase, using the undamaged strand as a template, and the nick is sealed by DNA ligase.

The choice between direct reversal and BER depends on the specific type of alkylation damage. For example, MGMT is highly effective at removing methyl groups from O6-guanine, but it is not effective at removing larger alkyl groups. In these cases, BER is the primary repair pathway.

DNA alkylation repair is essential for maintaining the integrity of the genome. Defects in this pathway can lead to increased mutation rates, genomic instability, and an increased risk of cancer. For example, mutations in MGMT have been linked to increased risk of glioblastoma, a type of brain cancer.

In addition to these two main pathways, there are other mechanisms that contribute to DNA alkylation repair, including nucleotide excision repair (NER), mismatch repair (MMR), and translesion synthesis (TLS). NER removes bulky DNA lesions, including some alkylated bases. MMR repairs mismatches in DNA that can arise from replication errors or from alkylation damage. TLS is a process that allows DNA replication to proceed past damaged bases, even if they are not repaired.

The repair of alkylated DNA is a complex process that involves multiple enzymes and pathways. These pathways work together to ensure that DNA damage is efficiently repaired and that the integrity of the genome is maintained.'
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Proteins (5)

Compounds (34)