Chlamydia Infection Promotes Host DNA Damage and Proliferation but Impairs the DNA Damage Response

• Ctr induces histone modifications reminiscent of DNA damage and cellular senescence (SAHF)
• Ctr-elicited ROS contribute to DNA double-strand breaks (DSBs), promoting SAHF formation
• DSBs associate with γH2AX, but DSB repair activities are suppressed in Ctr-infected cells
• Despite deficient DSB repair, Ctr-induced ERK and SAHF facilitate damaged cell proliferation

SummaryThe obligate intracellular bacterial pathogen Chlamydia trachomatis (Ctr) has been associated with cervical and ovarian cancer development. However, establishment of causality and the underlying mechanisms remain outstanding. Our analysis of Ctr-induced alterations to global host histone modifications revealed distinct patterns of histone marks during acute and persistent infections. In particular, pH2AX (Ser139) and H3K9me3, hallmarks of DNA double-strand breaks (DSBs) and senescence-associated heterochromatin foci (SAHF), respectively, showed sustained upregulation during Ctr infection. Ctr-induced reactive oxygen species were found to contribute to persistent DSBs, which in turn elicited SAHF formation in an ERK-dependent manner. Furthermore, Ctr interfered with DNA damage responses (DDR) by inhibiting recruitment of the DDR proteins pATM and 53BP1 to damaged sites. Despite impaired DDR, Ctr-infected cells continued to proliferate, supported by enhanced oncogenic signals involving ERK, CyclinE, and SAHF. Thus, by perturbing host chromatin, DSB repair, and cell-cycle regulation, Ctr generates an environment favorable for malignant transformation.

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