Targeting and processing of site‐specific DNA interstrand crosslinks

Abstract

DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, and thus ICL-inducing agents such as cyclophosphamide, melphalan, cisplatin, psoralen and mitomycin C have been used clinically as anti-cancer drugs for decades. ICLs can also be formed endogenously as a consequence of cellular metabolic processes. ICL-inducing agents continue to be among the most effective chemotherapeutic treatments for many cancers; however, treatment with these agents can lead to secondary malignancies, in part due to mutagenic processing of the DNA lesions. The mechanisms of ICL repair have been characterized more thoroughly in bacteria and yeast than in mammalian cells. Thus, a better understanding the molecular mechanisms of ICL processing offers the potential to improve the efficacy of these drugs in cancer therapy. In mammalian cells it is thought that ICLs are repaired by the coordination of proteins from several pathways, including nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), translesion synthesis (TLS), and proteins involved in Fanconi anemia (FA). In this review, we focus on the potential functions of NER, MMR, and HR proteins in the repair of and response to ICLs in human cells and in mice. We will also discuss a unique approach, using psoralen covalently linked to triplex-forming oligonucleotides to direct ICLs to specific sites in the mammalian genome.

SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability

“…DNA damage induced by cisplatin is repaired by several pathways, including nucleotide excision repair (NER), homologous recombination, and translesion synthesis (32). Suppression of ARID1A as well as ARID1B sensitized cells to cisplatin more significantly than IR but double knockdown of both ARID1 proteins did not increase the cellular sensitivity of single suppression (Fig.…”

Limited Repair of Critical DNA Damage in Cells Exposed to Low Dose Radiation

“…It should be noted that the cells of patients with the syndrome of Fanconi anemia (FA) are characterized by genome instability, and predisposition to malignancy, and by increased sensitivity to IR due to their inability to repair ICL of DNA (Alter, 2002;Kuhnert et al, 2009). ICL initiate the development of DDR with the activation of cell cycle checkpoints, with transmission of the signal along the chain ATM/ATR → Chk1/Chk2 → Cdc25 (A, B, C) → cyclin-CDK (Wu and Vasquez, 2008;Ben-Yehoyada et al, 2009;Vasquez, 2010). It has been also shown that the induction of ICL in DNA is accompanied by formation of γH2AX-foci (Huang et al, 2004;Mogi and Oh, 2006;Mogi et al, 2008).…”

Targeted gene correction using psoralen, chlorambucil and camptothecin conjugates of triplex forming peptide nucleic acid (PNA)

“…Psoralen can form DNA interstrand cross-links upon activation with UVA radiation, and the repair of such cross-links may involve DNA double strand breaks and/or recombination. [12][13][14] Chlorambucil readily forms mono-adducts (as well as some crosslinks) with dsDNA, 15 whereas camptothecin does not react with the DNA strand directly, but rather interfere with topoisomerase I activity by blocking the re-sealing of the DNA, which may eventually result in frank strand breaks. 16 Surprisingly, we find that sequence-targeted PNAs that can react covalently with the DNA helix exhibit a highly inhibitory effect on gene correction in nuclear extract and in a cell culture, extra-chromosomal assay.…”