Atm Function

In the past, individual deficits in DNA repair, genetic recombination, chromatin structure, and cell cycle checkpoint control all have been proposed as the underlying pathological defect in AT (reviewed in Ref. see 155). However, it now clear that much of the AT phenotype is caused by defects in signaling pathways that activate multiple cellular responses to DNA damage (155-160).

Prior to the cloning of the ATM gene, we proposed a model for AT in which the AT defect results in an inability to coordinately activate a group of diverse cellular functions in response to DNA damage (83,155). Figure 6 depicts a current version of this model, in which the detection of DSBs in DNA triggers an ATM-dependent signal transduction network, resulting in a kinase cascade that activates cellular functions that promote genetic stability by temporarily arresting the cell cycle and enhancing homologous recombination and other forms of DSB repair. At same time, the network modulates cellular survival by inhibiting execution of damage-induced programmed cell death in some cells while promoting it in others. These ATM-dependent responses allow cells to react to intentional DSBs created during meiosis and immune gene rearrangement as well as unintentional DSBs that result from stalled replication forks, aberrant telomeres, endogenous oxidative DNA damage, and environmental mutagens. In addition to the responses illustrated in Figure 6, there are likely to be other, as yet undefined, ATM-dependent functions. ATM-dependent pathways are presumed to function in meiotic, mitotic, and postmitotic cells.

Damage

I INTENTIONAL DNA BREAKS Metotfc Recombination Immune Gene Rearrangements Mobile Element Transposition

UNPLANNEO DNA BREAKS Exogenous Mutagens X-lnud laden radlomlmetlc chemicals Endogenous Mutagens Rsaothre Oxygen Species Aberrant Telomeres

Sensors Transducers & Effectors

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