A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites

Abstract

Interstrand DNA-DNA cross-links are highly toxic lesions that are important in medicinal chemistry, toxicology, and endogenous biology. In current models of replication-dependent repair, stalling of a replication fork activates the Fanconi anemia pathway and cross-links are “unhooked” by the action of structure-specific endonucleases such as XPF-ERCC1 that make incisions flanking the cross-link. This process generates a double-strand break, which must be subsequently repaired by homologous recombination. Recent work provided evidence for a new, incision-independent unhooking mechanism involving intrusion of a base excision repair (BER) enzyme, NEIL3, into the world of cross-link repair. The evidence suggests that the glycosylase action of NEIL3 unhooks interstrand cross-links derived from an abasic site or the psoralen derivative trioxsalen. If the incision-independent NEIL3 pathway is blocked, repair reverts to the incision-dependent route. In light of the new model invoking participation of NEIL3 in cross-link repair, we consider the possibility that various BER glycosylases or other DNA-processing enzymes might participate in the unhooking of chemically diverse interstrand DNA cross-links.

Frankenstein or a Submarine Alkaline Vent: Who Is Responsible for Abiogenesis?

“…We note again that extant life unfailingly meets its specificity requirements by managing essentially every chemical transformation it requires using macromolecular machines–machines functioning either as highly selective and specific catalysts (critically, allosterically controllable ones), or as disequilibrium converting nano‐engines (see below), or as dynamic structural elements. In addition it must invest heavily in sophisticated repair and waste disposal, including of course, that of spent electrons . Nothing is left to the indiscriminate and unselective fortunes of mass action solution chemistry.…”

Targeting BER enzymes in cancer therapy

“…Psoralen-induced monoadducts function as substrates for NEIL1 where HeLa cells deficient in NEIL1 and/or APE1 exhibit hypersensitivity to psoralen upon UVA photoactivation [130]. Furthermore, NEIL1 and NEIL3 have been shown to be involved in the repair of bulky psoralen-induced interstrand cross-links [131][132][133]. On the other hand, cisplatin cytotoxicity is attributed to inducing different types of DNA lesions including monoadducts, intrastrand and interstrand cross-links [134] in addition to resulting in an increased generation of ROS and oxidative DNA damage [28].…”

Integration of Emerging Biomedical Technologies in Meat Processing to Improve Meat Safety and Quality

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