p53 coordinates base excision repair to prevent genomic instability

Abstract

DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells.

Base excision repair of oxidative DNA damage from mechanism to disease

“…Although mutations that reduce the functionality of key enzymes have been shown to predispose patients to certain cancers, epidemiological studies suggest that even single nucleotide polymorphism (SNPs) far from the active site of such enzymes can alter cancer rates. It is perhaps even more surprising to consider that the upregulation of DNA repair enzymes, such as APE1, can actually increase the rate of mutation, accentuating the fact that BER is not a risk-free procedure (156). Alternatively, in a cell’s efforts to conserve one nucleotide in a gene, single strand breaks (among other highly reactive species) are created, which pave the way for even more catastrophic double strand breaks when a balance between the repair enzymes is not maintained (see Figure 7).…”

“…This break can be highly mutagenic if not processed properly. Therefore, not surprisingly, dysfunction in APE1 expression or activity has been associated with cancer (156). During times of higher genotoxic stress, such as multiple SSBs, the tumor suppressor p53 reduces the expression level of APE1.…”

“…This protects the genome from additional single stranded breaks, giving the cell time to properly repair the damage. In the greater than 50% of human cancers that contain p53 mutations abnormally high levels of APE1 could contribute to increased mutagenesis and tumor progression (156, 159). The post translational modification acetylation, which is thought to increase APE1’s activity, is elevated in primary tumor tissues, suggesting that minor changes in function without changes in expression can modify tumorigenesis (160).…”

The role of genomic instability and expression of the p53 protein gene network in the processes of oncogenesis in first- and second-generation children living in radioactively contaminated areas

“…В настоящей работе для дальнейшего изучения влияния радиационного фактора на состояние здо-ровья детей 1-го и 2-го поколений, подвергшихся воздействию радиации (в частности, влияния радиа-ционного фактора на онкогенез), методом Nanostring была исследована экспрессия генной сети белка р53, играющего важную роль в защите организма от фор-мирования онкологической патологии [16]. Как и любой ген, ген ТР53 вовлечен во взаимодействие с большим количеством других генов и их белковых продуктов, образуя с каждым из них отрицательные и положительные обратные связи в генной сети p53.…”

Estudo do papel de mTOR na regulação da atividade de reparo do DNA mitocondrial humano

“…Adicionalmente, como APE1 se transloca para o núcleo em resposta a estresse oxidativo (Ramana et al, 1998) estarem sob controle de mTORC2, através de sua influência em Akt, como p53 e NF-κB e CREB (revisto em Kelley et al, 2012). Em especial, algumas evidências apontam para um possível papel de p53 na regulação de BER, através de APE1 (Poletto et al, 2016 Similarmente, a diminuição da expressão de Polγ e TFAM também vai contra o esperado (Figuras 6, 7, 10 e 11), embora a diminuição da expressão de TFAM com inibição de mTORC1 já tenha sido observada na literatura (Morita et al, 2015).…”