p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice

DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes

Geometrically undistorted MRI in the presence of field inhomogeneities using compressed sensing accelerated broadband 3D phase encoded turbo spin-echo imaging

In this study, we explore the potential of compressed sensing (CS) accelerated broadband 3D phase-encoded turbo spin-echo (3D-PE-TSE) for the purpose of geometrically undistorted imaging in the presence of field inhomogeneities. To achieve this goal 3D-PE-SE and 3D-PE-TSE sequences with broadband rf pulses and dedicated undersampling patterns were implemented on a clinical scanner. Additionally, a 3D multi-spectral spin-echo (ms3D-SE) sequence was implemented for reference purposes. First, we demonstrated the influence of susceptibility induced off-resonance effects on the spatial encoding of broadband 3D-SE, ms3D-SE, 3D-PE-SE and 3D-PE-TSE using a grid phantom containing a titanium implant (Delta chi= 182 ppm) with x-ray CT as a gold standard. These experiments showed that the spatial encoding of 3D-PE-(T) SE was unaffected by susceptibility induced off-resonance effects, which caused geometrical distortions and/or signal hyper-intensities in broadband 3D-SE and, to a lesser extent, in ms3D-SE frequency encoded methods. Additionally, an SNR analysis was performed and the temporally resolved signal of 3D-PE-(T) SE sequences was exploited to retrospectively decrease the acquisition bandwidth and obtain field offset maps. The feasibility of CS acceleration was studied retrospectively and prospectively for the 3D-PE-SE sequence using an existing CS algorithm adapted for the reconstruction of 3D data with undersampling in all three phase encoded dimensions. CS was combined with turbo-acceleration by variable density undersampling and spherical stepwise T-2 weighting by randomly sorting consecutive echoes in predefined spherical k-space layers. The CS-TSE combination resulted in an overall acceleration factor of 60, decreasing the original 3D-PE-SE scan time from 7 h to 7 min. Finally, CS accelerated 3D-PE-TSE in vivo images of a titanium screw were obtained within 10 min using a micro-coil demonstrating the feasibility of geometrically undistorted MRI near severe field inhomogeneities

p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice.

Acknowledgements: We thank the Human Research Tissue Bank for processing histological samples. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. We would like to thank C. Knox, C. Watson, L. Tredgett, J. Clark, the Ares and Biomed staff for assistance with animal procedures and experimentation. We thank M. Daly, F. Zhang, P. Penttila and the Flow Cytometry Core staff for their technical assistance. We would like to thank C. Perez for assisting with the generation of RNA sequencing libraries. Funding was provided by the Medical Research Council as part of UK Research and Innovation file reference no. MC_UP_1201/18 (G.P.C., R.J.H, N.B., H.W. and A.C.) and Hubrecht Institute (J.I.G.), Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) project number OCENW.M20.113 (J.S.).DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes