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Genetic defects in crucial parts of this network lead to a group of human genetic disorders that are collectively called genomic instability syndromes. These diseases are characterized by degeneration of specic tissues, sensitivity to particular DNA damaging agents, chromosomal instability and a marked predisposition to cancer.The extremely cytotoxic DSB is induced by ionizing radiation, radiomimetic chemicals and oxygen radicals formed in the course of normal metabolism, and can also follow replication fork stalling.This complex signaling network works swiftly to affect numerous cellular systems. One of its hallmarks is the activation of cellcycle checkpoints, which temporarily halt the cell cycle while the damage is assessed and repaired. The sudden arrest of the cell cycle involves marked alterations in numerous physiological processes.Here, I summarize recent work that has provided new insights into the different tiers of this process.These sensors transmit a signal to transducers, which in turn convey the signal to numerous downstream effectors involved in specic pathways. Additional factors in the sensor tier of the DSB response are recruited to the damaged sites, where they create rapidly expanding nuclear foci and take part in signaling damage to the transducers.The primary transducer of the DSB alarm is the nuclear protein kinase ataxiatelangiectasia mutated. In response to DSB induction, ATM is rapidly activated and phosphorylates various substrates, each of which is a key factor in a damageresponse pathway.The clinical phenotype associated with loss of ATM activity is that of a buy glutamic acid prominent genomic instability syndrome ataxia telangiectasia. Another member of the PIKK Targetmol‘s glutamic acid family is TRRAP, a protein component of histone acetyltransferase complexes that does not possess protein kinase activity. The PIKK protein kinases, which are conserved from yeast to mammals, respond to various stresses by phosphorylating substrates in the appropriate pathways.Whereas ATM and ATR share substrates in the DSB response, they show selective substrate specicities in response todifferent genotoxic stresses and DSB inducers. ATM and ATR: distinct and cooperative roles ATR has a role in damage surveillance at the DNA replication fork and might bedirectly involved in regulating replication progression. The functional relationships between ATM and ATR in the DSB response have turned out to be more complex than was previously thought.It is generally assumed that after the rapid activation of ATM in response to DSB induction and the subsequent phosphorylation of its numerous substrates, ATR is independently triggered and maintains phosphorylation of some of these substrates.This functional redundancy is observed in AT cells, which are devoid of ATM activity but can mount a belated, moderate DSB response that could be ascribed to ATR.Thus, ATM and ATR have been thought to act in parallel, independently of each other.Binding of ATR to these sites is mediated by an interaction between the ATR accessory protein ATRIP and replication protein A, which coats the singlestranded ends.By contrast, the response of ATR to UV lesions and stalled replication forks occurs independently of ATM.These observations place ATM upstream of ATR in some phases of the cell cycle, in addition to their functional redundancy. Separate and overlapping roles of ATM and ATR in responses to genotoxic stress.
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