Base Excision Repair Variants in Cancer

Abstract

Base excision repair (BER) is a key genome maintenance pathway that removes endogenously damaged DNA bases that arise in cells at very high levels on a daily basis. Failure to remove these damaged DNA bases leads to increased levels of mutagenesis and chromosomal instability, which have the potential to drive carcinogenesis. Next Generation sequencing efforts of the germline and tumors genomes of thousands of individuals has uncovered many rare mutations in BER genes. Given that BER is critical for genome maintenance, it is important to determine whether BER genomic variants have functional phenotypes. In this chapter we present our in silico methods for the identification and prioritization of BER variants for further study. We also provide detailed instructions and commentary on the initial cellular assays we employ to dissect potentially important phenotypes of human BER variants and highlight the strengths and weaknesses of our approaches. BER variants possessing interesting functional phenotypes can then be studied in more detail to provide important mechanistic insights regarding the role of aberrant BER in carcinogenesis.

Prognostic Value of SLC4A4 and its Correlation with Immune Infiltration in Colon Adenocarcinoma

“…Microsatellite instability can also predict tumor resistance to certain chemotherapeutic agents, such as immune checkpoint inhibitors [ 46 ]. Base excision repair is critical for removing endogenously damaged DNA bases, with failure to remove these bases leading to chromosomal instability and tumor development [ 47 ].…”

NMR and computational methods for molecular resolution of allosteric pathways in enzyme complexes

“…Within short patch BER, pol β identifies and repairs gapped DNA by recruiting and inserting a deoxynucleoside triphosphate (dNTP). The ability of pol β to accurately discern matched (correct) versus mismatched (incorrect) base pairs is integral to its function, highlighted by the fact that over 30% of human cancers have mutations in the gene encoding pol β (Marsden et al 2017;Starcevic et al 2004). Many of these cancer-linked mutations lead to a loss of function; however, several mutations maintain near wildtype (WT) catalytic efficiency with vastly altered fidelity and have been termed "mutator variants."…”

“…Many of these cancer-linked mutations lead to a loss of function; however, several mutations maintain near wildtype (WT) catalytic efficiency with vastly altered fidelity and have been termed "mutator variants." Expression of pol β mutants within healthy mammalian cells has been shown to cause cellular transformation and metastasis (Marsden et al 2017;Murphy et al 2012;Wallace et al 2012); thus, there is great interest in elucidating the mechanistic underpinnings of the pol β selection process, particularly the allosteric component by which binding of the appropriate nucleotide is regulated. Several reviews (Barakat et al 2012;Wilson 2006, 2014;Hakem 2008; Yamtich and Sweasy 2010) have rigorously described the known molecular mechanism and structure of pol β and related polymerases; therefore, we will only highlight important NMR and computational studies that have improved the understanding of allosteric regulation underlying its nucleotide selection.…”

POM121 overexpression is related to a poor prognosis in colorectal cancer

“…The regulatory function of POM121 in transcription factors allows it to disturb the homeostasis of cellular signaling crucial for carcinogenesis [30].Mismatch repair proteins are reported to initiate DNA hypermethylation alteration and tumorigenesis [31]. Base excision repair is a key pathway that removes damaged DNA bases, with the potential to drive carcinogenesis [32]. POM121 showed close relationships with DNA replication, mismatch repair and base excision repair, suggesting that POM121 may promote CRC oncogenesis by modulating DNA replication and repair.…”