Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity

Abstract

DNA of living cells is always exposed to damaging factors. To counteract the consequences of DNA lesions, cells have evolved several DNA repair systems, among which base excision repair is one of the most important systems. Many currently used antitumor drugs act by damaging DNA, and DNA repair often interferes with chemotherapy and radiotherapy in cancer cells. Tumors are usually extremely genetically heterogeneous, often bearing mutations in DNA repair genes. Thus, knowledge of the functionality of cancer-related variants of proteins involved in DNA damage response and repair is of great interest for personalization of cancer therapy. Although computational methods to predict the variant functionality have attracted much attention, at present, they are mostly based on sequence conservation and make little use of modern capabilities in computational analysis of 3D protein structures. We have used molecular dynamics (MD) to model the structures of 20 clinically observed variants of a DNA repair enzyme, 8-oxoguanine DNA glycosylase. In parallel, we have experimentally characterized the activity, thermostability, and DNA binding in a subset of these mutant proteins. Among the analyzed variants of 8-oxoguanine DNA glycosylase, three (I145M, G202C, and V267M) were significantly functionally impaired and were successfully predicted by MD. Alone or in combination with sequence-based methods, MD may be an important functional prediction tool for cancer-related protein variants of unknown significance.

Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain

“…Finally, novel functional implications of APE1 in DNA regulatory processes have been unveiled recently. On the one hand, APE1 participates in the BER pathway-mediated correction of mutagenic T:G mismatches generated when 5-methylcytosine, the key DNA epigenetic mark, is spontaneously deaminated, becoming a thymine [13]. On the other hand, APE1 has been recently shown to regulate the formation of G-quadruplex (G4) structures in guanine-rich DNA sequences [14].…”

“…Although the structural role of the N-terminal tail of APE1 is still to be established, mounting evidence points to this region as a key feature in APE1 activity and regulation [13,26,55,56].…”

“…In addition to acting as a DNA repair protein, APE1 also fulfils additional functions. In fact, it was independently discovered as a redox factor regulating the DNA binding of several transcription factors involved in different growth signalling pathways [10] and was subsequently found to also be involved in additional genetic regulatory mechanisms [11][12][13][14]. For instance, it acts as a transcriptional repressor through interaction with negative calcium-response elements (nCaRE) [12].…”

UV Protection in the Cornea: Failure and Rescue

“…One of these lesions, 8-Oxoguanine (8-OxoG) in particular is linked to greater cancer cell survival [ 124 ]. The base excision repair (BER) process that repairs such damage begins with detecting the lesion via DNA glycosylases, in the case of 8-OxoG, Oxoguanine glycosylase 1 (OGG1) binds to the lesion [ 125 ]. The DNA glycosylase then cleave the oxidised base out of the DNA, causing a single-strand break.…”

A dissected LMO2 functional analysis and clinical relevance in brain gliomas

“…During the past decade, many efforts have been made to promote data-driven approaches for precision medicine in cancer research field including brain gliomas [ 12 ], including the usage of genetic multi-omics data, radiomics data, protein structure data and a variety of clinical data [ [13] , [14] , [15] , [16] ]. In this study, we aimed to address a full view of functional and clinical significance of the pivotal oncogenic gene LMO2 in gliomas primarily with a Weighted Gene Co-Expression Network Analysis (WGCNA) based bioinformatical strategy, and the results did give a well resolution of LMO2 functions in such complicated tumor environments.…”