Structural elucidation of a DNA cross-link repair mechanism involving NEIL3 protein
DNA interstrand cross-links (ICLs) are covalent linkages between nucleotides formed by various endogenous and exogenous sources such as cisplatin or a simple oxidative stress. ICLs are very harmful as they pose impenetrable barriers to DNA replication. That’s why cells have developed special DNA repair pathways to remove these lesions. One of them recruits NEIL3, a DNA glycosylase utilizing several zinc finger domains for the ICL repair.
An interdisciplinary team from Evžen Bouřa Group and Pavlína Maloy Řezáčová Group at IOCB Prague led by Jan Šilhán investigated the molecular architecture of recognition of the stalled replication fork by NEIL3 DNA glycosylase during DNA repair pathway.
Through biochemical and NMR measurements they showed that the NEIL3 zinc-finger domains recognize not only ssDNA as reported previously but also very short replication-fork intermediates. To better understand the repair mechanism, the scientists crystallized and solved the structure of the NEI domain from mouse NEIL3 protein, covalently trapped with the DNA substrate.
Thanks to that they constructed a DNA repair model of NEIL3 bound to the replication fork in the intermediate state. These results could lead to targeted uses of ICL-inducing agents in cancer treatment.
Original article: Huskova, A.; Dinesh, D. C.; Srb, P.; Boura, E.; Veverka, V.; Silhan, J. Model of abasic site DNA cross-link repair; from the architecture of NEIL3 DNA binding domains to the X-structure model. Nucleic Acids Res. 2022. https://doi.org/10.1093/nar/gkac793