title: Differential impact of mouse Rad9 deletion on ionizing radiation-induced bystander effects.
abstract: The cellular response to ionizing radiation is not limited to cells irradiated directly but can be demonstrated in neighboring "bystander" populations. The ability of mouse embryonic stem (ES) cells to express a bystander effect and the role of the radioresistance gene Rad9 were tested. Mouse ES cells differing in Rad9 status were exposed to broad-beam 125 keV/ microm 3He alpha particles. All populations, when confluent, demonstrated a dose-independent bystander effect with respect to cell killing, and the Rad9-/- genotype did not selectively alter that response or cell killing after direct exposure to this high-LET radiation. In contrast, relative to Rad9+/+ cells, the homozygous mutant was sensitive to direct exposure to alpha particles when in log phase, providing evidence of a role for Rad9 in repair of potentially lethal damage. Direct exposure to alpha particles induced an increase in the frequency of apoptosis and micronucleus formation, regardless of Rad9 status, although the null mutant showed high spontaneous levels of both end points. All populations demonstrated alpha-particle-induced bystander apoptosis, but that effect was most prominent in Rad9-/- cells. Minimal alpha-particle induction of micronuclei in bystander cells was observed, except for the Rad9-/- mutant, where a significant increase above background was detected. Therefore, the Rad9 null mutation selectively sensitizes mouse ES cells to spontaneous and high-LET radiation-induced bystander apoptosis and micronucleus formation, but it has much less impact on cell killing by direct or bystander alpha-particle exposure. Results are presented in the context of defining the function of Rad9 in the cellular response to radiation and its differential effects on individual bystander end points.
authors.affiliation: Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhu
authors.forename: Hongning
authors.initials: H
authors.lastname: Zhou
authors.forename: Corinne
authors.initials: C
authors.lastname: Leloup
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Marino
authors.forename: Charles R
authors.initials: CR
authors.lastname: Geard
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.forename: Howard B
authors.initials: HB
authors.lastname: Lieberman
mesh_terms: D000512:Alpha Particles; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D024201:Bystander Effect / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000502:physiology*; D004249:DNA Damage; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects
chemical_list: D018797:Cell Cycle Proteins; C069930:rad9 protein