Temporally distinct roles of ATM and ROS in genotoxic- stress-dependent induction and maintenance of cellular senescence

Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS). Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence. Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells. Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence. By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM. Inhibition or removal of either of the components caused cell death in senescent cells, through a deregulated ATM-ROS axis. Overall, our work demonstrates existence of an intricate temporal hierarchy between genotoxic stress, DDR and ROS in cellular senescence. Our model reports the existence of different stages of cellular senescence with distinct regulatory networks.

Dynamical generation of flavour

We propose the generation of Standard Model fermion hierarchy by the extension of renormalizable SO(10) GUT with O(N (g) ) family gauge symmetry. In this scenario, Higgs representations of SO(10) also carry family indices and are called Yukawons. Vacuum expectation values of these Yukawon fields break GUT and family symmetry and generate MSSM Yukawa couplings dynamically. We have demonstrated this idea using Higgs irrep, ignoring the contribution of 1 2 0-plet which is, however, required for complete fitting of fermion mass-mixing data. The effective MSSM matter fermion couplings to the light Higgs pair are determined by the null eigenvectors of the MSSM-type Higgs doublet superfield mass matrix . A consistency condition on the doublet (1,2,+/- 1]) mass matrix ( 0) is required to keep one pair of Higgs doublets light in the effective MSSM. We show that the Yukawa structure generated by null eigenvectors of are of generic kind required by the MSSM. A hidden sector with a pair of (S (a b) ; I center dot (a b) ) fields breaks supersymmetry and facilitates 0. SUSY breaking is communicated via supergravity. In this scenario, matter fermion Yukawa couplings are reduced from 15 to just 3 parameters in MSGUT with three generations.