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Review
.2021 Jan 15;22(1):47-62.
doi: 10.1631/jzus.B2000344.

DNA alkylation lesion repair: outcomes and implications in cancer chemotherapy

Affiliations
Review

DNA alkylation lesion repair: outcomes and implications in cancer chemotherapy

Yihan Peng et al. J Zhejiang Univ Sci B..

Abstract

Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage is cytotoxic and potentially mutagenic. Alkylation chemotherapy is a major therapeutic modality for many tumors, underscoring the importance of the repair pathways in cancer cells. Several different pathways exist for alkylation repair, including base excision and nucleotide excision repair, direct reversal by methyl-guanine methyltransferase (MGMT), and dealkylation by the AlkB homolog (ALKBH) protein family. However, maintaining a proper balance between these pathways is crucial for the favorable response of an organism to alkylating agents. Here, we summarize the progress in the field of DNA alkylation lesion repair and describe the implications for cancer chemotherapy.

Keywords: AlkB homolog (ALKBH); Alkylation repair; Base excision repair; Methyl-guanine methyltransferase (MGMT).

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Figures

Fig. 1
Fig. 1.Essential repair mechanisms for alkylation lesions. (a) Repair of anN-alkyl DNA lesion by multi-step base excision repair (BER). In cells, BER can occur in two sub-pathways: short-patch or long-patch BER. In both sub-pathways, theN-methyl base adduct is first removed by alkyladenine-DNA glycosylase (AAG) to generate an abasic (AP) site. Then, the AP site is cleaved by the AP endonuclease (APE) to generate a single-strand break (SSB) with flapped 5'-deoxyribose phosphate (5'-dRP) or flapped 3'-hydroxyl (3'-OH). In short-patch BER, DNA polymerase β (Pol β) can remove the 5'-dRP moiety and fill in the gap; then ligase III (LIG III) ligates the gap into the existing DNA. This process is coordinated by the scaffold activity of X-ray repair cross-complementing group 1 (XRCC1). Additionally, poly(ADP-ribose) polymerase 1 (PARP1) may help to recruit the XRCC complex. In long-patch BER, DNA polymerase δ/ε (Pol δ/ε) recruited by proliferating cell nuclear antigen (PCNA) synthesizes DNA to fill in the gap, leaving a long stretch of nascent DNA. Then, flap endonuclease 1 (FEN1) removes stretch from the bases. Finally, ligase I (LIG I) ligates the gap and the repair is finished. (b) Direct reversal of anO-alkyl DNA lesion byO6-methylguanine-DNA methyltransferase (MGMT). The methyl group on theO-methyl base adduct is directly transferred to a catalytic residue of MGMT. Next, MGMT is ubiquitinated and subject to proteasome degradation. (c) Direct demethylation of anN-alkyl lesion by AlkB homolog (ALKBH) demethylase.
Fig. 2
Fig. 2. Biological effects of alkylated purine repair. (a) Consequences ofN-alkyl lesion repair by base excision repair (BER) within a double-stranded DNA (dsDNA) context. Several types of originalN-alkyl lesions are not inherently toxic and can be tolerated by cells. Removal ofN-methyl DNA base adducts by alkyladenine-DNA glycosylase (AAG) generates toxic abasic (AP) sites. High AAG activity in cells leads to accumulation of AP sites, which will lead to replication fork block or collapse, and ultimately to cell death. However, the translesion synthesis (TLS) mechanism can bypass AP sites to protect cells from death, but with more mutations. Defects in BER efficiency caused by deficiency in certain BER factors (AP endonuclease 1 (APE1), poly(ADP-ribose) polymerase 1 (PARP1), X-ray repair cross-complementing group 1 (XRCC1), polymerase β (Pol β), ligase III (LIG III), flap endonuclease 1 (FEN1), etc.) will cause accumulation of toxic intermediates, which also leads to replication fork block or collapse, followed by cell death. (b) Consequences ofN-alkyl lesion repair within a single-stranded DNA (ssDNA) context. When anN-methyl DNA base adduct presents in ssDNA, it is first recognized and removed by AAG to generate AP sites, which blocks replication. TLS can bypass such blocks to protect cells, but with more mutations. APE-mediated AP site resection leads to the generation of double-strand breaks (DSBs). The homologous recombination (HR) mechanism can tolerate the cytotoxicity of DSBs, otherwise this would lead to cell death. Alternatively, the AP site generated in the ssDNA can be protected by formation of a 5-hydroxymethylcytosine (5hmC) binding, ES-cell-specific (HMCES)-DNA complex, which will eventually be resolved by proteasome degradation.
Fig. 3
Fig. 3. Biological effects ofO-alkyl lesion repair. TheO-alkyl lesion can be directly repaired byO6-methylguanine-DNA methyltransferase (MGMT). If the lesion is not properly repaired, DNA replication at the lesion site will introduce mispairs, which can be recognized by the MutSα-MutLα complex and activate mismatch repair (MMR) signaling. The futile cycles of DNA resection and resynthesis can cause replication fork collapse and double-strand break (DSB) formation, which can ultimately lead to cell death. Meanwhile, the mispair recognized by the MutSα-MutLα complex can directly activate ataxia telangiectasia-mutated and Rad3-related (ATR) kinase and induce the ATR-CHK1 (checkpoint kinase 1) checkpoint, which can also contribute to cell death.
Fig. 4
Fig. 4.AlkB homolog 3 (ALKBH3)-dependent repair pathway. (a) Recruitment of ALKBH3 by transcription machinery. When the alkylation lesion is buried in double-stranded DNA (dsDNA), it may require transcription machinery to recognize and initiate the repair. RNA polymerase II (RNA Pol-II) will pause at the alkylated lesion, allowing really interesting new gene finger protein 113A (RNF113A) to ubiquitinate several proteins in the transcription complex. This ubiquitination chain can subsequently recruit the activating signal co-integrator complex (ASCC) complex. Finally, the ASCC complex unwinds the DNA and guides ALKBH3 to repair the lesion. (b) Recruitment of ALKBH3 to 3'-tailed DNA. If the alkylation lesion presents adjacent to double-strand break (DSB), it will first allow the end resection to generate the 3'-tailed DNA. Subsequently, DNA repair protein RAD51 homologC (RAD51C) binds the 3'-tailed DNA and guides ALKBH3 to repair the lesion.
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