Trends in Biochemical Sciences
The ATM-mediated DNA-damage response: taking shape
Section snippets
The DNA-damage response: repair and signaling
DNA damage is a serious threat to cellular homeostasis because it compromises one of its cornerstones – namely, the stability and integrity of the cellular genome. Sequence alterations in DNA arise from normal genomic transactions, spontaneous chemical changes in DNA constituents, replication errors, and endogenous and exogenous agents that inflict damage on the DNA. The greatest challenge to genome stability comes from these last agents, which induce various types of DNA lesion [1]. If not
From sensors to transducers
Mounting evidence indicates that dissemination of the DNA-damage alarm is based on a signal transduction mechanism that begins with ‘sensor’ proteins that sense the damage and/or chromatin alterations that occur after damage induction. These sensors transmit a signal to ‘transducers’, which in turn convey the signal to numerous downstream ‘effectors’ involved in specific pathways 3, 4, 5.
A well-studied sensor in mammalian cells is the Mre11–Rad50–Nbs1 (MRN) complex. This complex, comprising the
Dormant kinase becomes active
It has long been known that the kinase activity of ATM is enhanced by DSBs 53, 54. In a seminal study, Bakkenist and Kastan [55] showed that in unprovoked cells ATM is present as inert dimers or multimers that, after DNA damage, release highly active ATM monomers. During this process, ATM undergoes intermolecular autophosphorylation on Ser1981 [55]. Activated ATM has been recently shown to undergo additional phosphorylation events (M. Lavin, the 2005 Ataxia Telangiectasia Workshop, Belgirate,
Downstream of ATM: an ever-expanding network
The list of reported ATM substrates is far from complete, and many ATM-dependent responses are likely to involve ATM targets that are currently unknown. Nevertheless, the study of these pathways has revealed the diversity of the ATM-dependent response to DSBs (Figure 3).
In addition to the versatility of ATM as a protein kinase with numerous substrates, the ATM signaling network contains protein kinases that are themselves capable of targeting several downstream effectors simultaneously and, as
Concluding remarks and future directions
Investigations into the cellular response to DSBs continue to provide the most comprehensive view of how cells respond to DNA damage, in addition to detailed mechanistic insights into this elaborate response. Each of the three tiers of this signaling system provides many research directions. In particular, several questions remain open about the nature of the initial signal sent from DSBs to the MRN complex, which seems to be the first molecule to rush to the damaged sites and to start the
Acknowledgements
Present and previous work in the author's laboratory has been supported by The A-T Medical Research Foundation, The A-T Children's Project, The Israel Science Foundation, The National Institutes of Health (R01 NS31763), Israel Ministry of Science and Technology, The A-T Medical Research Trust, The Joint German-Israeli Project on Cancer Research, The A-T Ease Foundation and the Israeli Association for Fighting A-T.
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