Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4TopBP1

The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin-dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint

Exploring the neutrino mass matrix at M_R scale

We discuss the neutrino mass matrix which predicts zero or small values of |V_{13}| in MSSM and found the inequality, sin^2 2theta_{12} <= sin^2 2theta_sol, where sin^2 2theta_{12} is the mixing angle at M_R scale and sin^2 2theta_{sol} is the value determined by the solar neutrino oscillation. This constraint says that the model which predicts a larger value of tan^2 theta_{sol} at M_R than the experimental value is excluded. In particular, the bi-maximal mixing scheme at M_R scale is excluded, from the experimental value tan^2 theta_sol<1. In this model, |V_{13}| and a Dirac phase at m_Z are induced radiatively and turn out to be not small. The effective neutrino mass is expected to be of order 0.05 eV.Comment: revtex4, 20 pages, 6 figure

The Problem of Large Leptonic Mixing

Unlike in the quark sector where simple $S_3$ permutation symmetries can generate the general features of quark masses and mixings, we find it impossible (under conditions of hierarchy for the charged leptons and without considering the see-saw mechanism or a more elaborate extension of the SM) to guarantee large leptonic mixing angles with any general symmetry or transformation of only known particles. If such symmetries exist, they must be realized in more extended scenarios.Comment: RevTeX, 4 pages, no figure

Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients

The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation