New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps

Abstract

Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of nucleotide bases, represents a paradigm for the multifaceted roles of complex DDR in human cells. This review will focus on what is known about the canonical and non-canonical functions of BER enzymes related to cancer development, highlighting novel opportunities to understand the biology of cancer and representing future perspectives for designing new anticancer strategies. We will specifically focus on APE1 as an example of a pleiotropic and multifunctional BER protein.

Enzymatically active apurinic/apyrimidinic endodeoxyribonuclease 1 is released by mammalian cells through exosomes

“…APE1 is a multifunctional protein that participates in DNA repair and in the regulation of gene expression. We have recently demonstrated its role in RNA processing, as a major APendonuclease on abasic RNA 18,24,51 and on abasic ribonucleotides embedded in DNA 24,51 . Noteworthy, this unexpected activity on RNA possibly plays an important role in miRNAs processing, modulating gene expression under genotoxic stress conditions 18 .…”

“…For all these reasons, it can be hypothesized that a dis-regulation of APE1 expression may contribute to tumor development and progression through mechanisms independent from the canonical DNA repair function 18 . APE1 is also emerging as an important predictive factor being associated with chemoresistance phenomena due to its positive role in expression of cancer resistance genes, like MDR1 and others 23,24 .…”

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

“…Recent advancements in ultrasensitive next generation sequencing (NGS) disclosed the unusual accumulation of mitochondria DNA (mtDNA) mutations within the brain of patients with AD, which is believed to be due to accumulation of damaged mitochondria in neurons [176,177]. Additionally, base excision repair (BER) and DNA double-strand break repair (DSBR) are two major DNA repair pathways in neurons, which are downregulated in AD [178][179][180][181]. Interestingly, Ataxia Telangiectasia Mutated (ATM), a DNA repair gene downregulated in AD, plays an important role in autophagy and mitophagy [182,183].…”

Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN

“…Besides high penetrance mutations of genes in heredofamilial colon cancer, such as APC , MUTYH and those encoding proteins of the MMR, P53 and MDM2 families, polymorphisms could be definitely considered candidate risk factors for CRC [ 11 ]. Additionally, our recent publication demonstrated that base excision repair (BER) enzymes expression, including DNA glycosylases, APE1 and Pol ß, resulted in altered in CRC [ 12 , 13 ].…”