title: Chlamydia infection promotes host DNA damage and proliferation but impairs the DNA damage response.
abstract: The 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.
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
authors.forename: Cindrilla
authors.initials: C
authors.lastname: Chumduri
authors.forename: Rajendra Kumar
authors.initials: RK
authors.lastname: Gurumurthy
authors.forename: Piotr K
authors.initials: PK
authors.lastname: Zadora
authors.forename: Yang
authors.initials: Y
authors.lastname: Mi
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
mesh_terms: D002690:Chlamydia Infections / Q000473:pathology*; D002692:Chlamydia trachomatis / Q000472:pathogenicity*; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity
chemical_list: D017382:Reactive Oxygen Species; D045643:DNA Repair Enzymes