Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome

Measurements of double differential cross sections of secondary heavy charged particles induced by 70 MeV protons for microdosimetry study

Energy-differential cross sections of fragment (heavier than a-particle) production of carbon and aluminum were obtained with a specially designed Bragg curve spectrometer (BCS) and energy-time-of-flight method (E-TOF) for 70 MeV protons at 30-degree laboratory angle. The consistency of these two methods was confirmed by comparing Z=2 results each other. The energy differential cross sections of fragments for Z=3 and m=6, 7 are obtained by BCS and E-TOF, respectively. These results are compared with other experimental data, LA-150 evaluated nuclear data and QMD calculation results. The disagreements between present data and both results of evaluation and calculation show systematic trends

Extension of energy acceptance of Bragg curve counter at the high-energy end

We have developed an energy-extension method of a Bragg curve counter (BCC) at the high-energy end for the measurements of double-differential cross-sections (DDXs) of fragment productions induced by tens of MeV protons. In this method, we estimate the incident energies of the fragments penetrating a BCC on the basis of the energy loss and atomic number (Z). We applied this method to the DDX measurements of the natC(p, Li) and natC(p, Be) reactions induced by 70MeV protons. The validity of this method has been confirmed by comparing the DDXs of beryllium with theoretical predictions of the PHITS code and the two-body kinematics. This method improves the energy acceptance of the BCC for light fragments twice as wide as that of a conventional method without remodeling of the BCC and any loss of the original advantages

A Bragg curve counter with an active cathode to improve the energy threshold in fragment measurements

We have developed a Bragg curve counter (BCC) equipped with an active cathode to extend the energy acceptance to lower energies than for a conventional BCC to measure differential cross-sections of fragment production reactions induced by tens of MeV protons. The signal from the active cathode providing the timing signal of fragment incidence and the time difference signal between the cathode and anode gives information on the fragment range in the BCC on the basis of electron drift time. Utilization of the range information made possible identification of fragments less than 0.5 MeV/u that is lower than the identification threshold of a conventional BCC technique.After investigations on fundamental properties of a newly constructed BCC using heavy ion beams and alpha-particles, this method was applied successfully to a fragment production measurement for 70MeV proton-induced reactions on carbon. With this technique, the energy threshold of the BCC was improved without introducing an additional detector or energy loss

Double Differential Hydrogen and Helium Production Cross Section of Oxygen and Nitrogen for 75MeV Neutrons

International Conference on Nuclear Data for Science and Technolog

Double Differential Hydrogen and Helium Production Cross Section of Oxygen and Nitrogen for 75MeV Neutrons

International Conference on Nuclear Data for Science and Technolog