Abstract
Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70−/− mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesized that Bax-mediated apoptosis would be enhanced in the absence of Ku70 and contribute to premature death observed in ku70−/− mice. Here, we show that ku70−/− bax+/− and ku70−/− bax−/− mice have better survival, especially in females, than ku70−/− mice, even though Bax deficiency did not decrease the incidence of lymphoma observed in a Ku70-null background. Moreover, we found that ku70−/− mice develop lung diseases, like emphysema and pulmonary arterial (PA) occlusion, by 3 months of age. These lung abnormalities can trigger secondary health problems such as heart failure that may account for the poor survival of ku70−/− mice. Importantly, Bax deficiency appeared to delay the development of emphysema. This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion. Furthermore, the underlying mechanisms of emphysema and pulmonary hypertension due to PA occlusion are not well understood, and therefore ku70−/− and Bax-deficient ku70−/− mice may be useful models to study these diseases.
Highlights
Ku70 (Lupus Ku autoantigen p70) is a subunit of the Ku protein complex that plays an essential role in the nonhomologous end joining (NHEJ) pathway for DNA double-strand break (DSB) repair
Previous studies have shown that Ku70 has anti-apoptotic activity by suppressing the intrinsic cell death signal mediated by Bcl-2-associated protein X (Bax), in addition to its role in NHEJ DNA DSB repair.[8]
As p53 is intact in Baxdeficient Ku70-null mice, we speculate that p53 is able to suppress tumorigenesis caused by deficient NHEJ through p21-mediated cell cycle arrest and cellular senescence
Summary
Ku70 (Lupus Ku autoantigen p70) is a subunit of the Ku protein complex that plays an essential role in the nonhomologous end joining (NHEJ) pathway for DNA double-strand break (DSB) repair (reviewed in Downs and Jackson[1]). Ku70 has multiple biological activities independent of its role in the nucleus as a subunit of the Ku protein complex.[1]. Ku70 is known to have anti-apoptotic activity by suppressing the intrinsic cell death pathway[8] mediated by the pro-apoptotic. Bcl-2 family of proteins, such as Bax (Bcl-2-associated protein X).[9,10] Ku70-deficient cells have increased sensitivities to apoptotic stresses that are not limited to DNA-damaging stresses,[8,11,12] consistent with its anti-apoptotic activity
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