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Free keywords:
DNA damage response; DNA double strand breaks; ATM, PP2A; homologous
recombination repair; infection
Abstract:
Cervical and ovarian cancers exhibit characteristic mutational signatures that are reminiscent of mutational processes, including defective homologous recombination (HR) repair. How these mutational processes are initiated during carcinogenesis is largely unclear. Chlamydia trachomatis (Ctr) infections are epidemiologically associated with cervical and ovarian cancers.
Previously, we showed that Ctr induces DNA double-strand breaks (DSBs) but suppresses ATM activation and cell cycle checkpoints. The mechanisms by which ATM regulation is modulated and its consequences for the repair pathway in Ctr-infected cells remains unknown. Here, we found that Chlamydia interferes with the usual response of protein phosphatase 2A (PP2A) to DSBs. As a result, PP2A activity remains high as the level of inhibitory phosphorylation at Y307 remains unchanged following Ctr-induced DSBs. Protein-protein interaction analysis revealed that Ctr facilitates persistent interaction of PP2A with ATM, thus suppressing ATM activation.
This correlated with a remarkable lack of homologous recombination (HR) repair in Ctr-infected cells. Chemical inhibition of PP2A activity in infected cells released ATM from PP2A, resulting in ATM phosphorylation. Activated ATM was then recruited to DSBs and initiated downstream signaling, including phosphorylation of MRE11, NBS1 and Chk2-mediated activation of the G2/M cell cycle checkpoint in Ctr-infected cells. Further, PP2A inhibition led to the restoration of Ctr-suppressed HR DNA-repair function. Together, this study reveals that Ctr modulates PP2A signaling to suppress ATM activation to prevent cell cycle arrest, thus contributing to a deficient high fidelity HR pathway and a conducive environment for mutagenesis.
