Chlamydia trachomatis impairs host base excision repair by downregulating polymerase β

Abstract

Chlamydia trachomatis infections have been associated with ovarian cancer by several epidemiological studies. Here, we show that C. trachomatis‐infected primary human ovarian epithelial cells display elevated oxidative DNA damage. Base excision repair, an important cellular mechanism to repair oxidative DNA lesions, was impaired in infected primary ovarian and in several other types of cells. Polymerase β was downregulated in infected cells associated with upregulation of microRNA‐499a (miR‐499a). Stabilising polymerase β by inhibiting miR‐499a significantly improved repair. Moreover, downregulation of tumour suppressor p53 also resulted in attenuated repair in these cells. Thus, our data show that downregulation of polymerase β by direct inhibition through miR‐499a and downregulation of p53 debilitate the host‐cell base excision repair during C. trachomatis infection.

High-Grade Serous Ovarian Cancer—A Risk Factor Puzzle and Screening Fugitive

“…The presence of chlamydial plasmid-encoded Pgp3 (virulence factor in genital tract) antibody was associated with a doubled risk of ovarian cancer [72]. The mechanistic explanation for the relation between Chlamydia infection and ovarian cancer is based on the observations that infection provokes oxidative DNA damage, the down-regulation of p53 function, and induces DNA double-strand breaks [73,74]. Moreover, chlamydial infection causes an epithelial-to-mesenchymal transition (EMT) in host cells and increases the stemness and CpG methylation of genes.…”

“…[ 73,74] Proteobacteria and Firmicutes were present in 52% and 22% of ovarian cancer samples, respectively. The Proteobacteria/Firmicutes ratio was significantly increased in ovarian cancer samples…”

Is There a Hidden Burden of Disease as a Result of Epigenetic Epithelial-to-Mesenchymal Transition Following Chlamydia trachomatis Genital Tract Infection?

“…As an obligate intracellular bacteria, CT modifies the host cell environment in order to persist through secretion of proteins into the cytosol which also have a potential pro-oncogenic effect [11,32]. CT infection not only inhibits apoptosis but also, through the production of reactive oxygen species, induces oxidative damage of DNA, the repair of which is also impaired by down regulation of base excision repair and nucleotide excision pathways which will eventually result in double strand breaks in DNA [11,[32][33][34][35]. Telomeres, the protective caps on chromosomes, are also damaged [11,36].…”

Chlamydia trachomatis and human herpesvirus 6 infections in ovarian cancer—Casual or causal?

“…Recent studies have shown that C . trachomatis impairs BER of damaged DNA by down-regulating polymerase beta [6]. Deficiency in BER pathway enables the cells to acquire tumorigenic properties [7].…”

“…C . trachomatis also changes the miRNA profile of the host cell such as by up-regulating miR-30c or miR-499a targeting DRP-1 and polymerase beta, respectively [6, 33]. Both miRNAs also target p53.…”