PubMed · 16044504
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Martin F Lavin. 2005. How important is ATM?. https://pubmed.ncbi.nlm.nih.gov/16044504/
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The DNA Damage Response (DDR) is a highly regulated process that safeguards genomic integrity against DNA lesions. Increasing evidence supports a reciprocal relationship between damaged chromatin architecture and the signalling pathways that coordinate the DDR. However, the mechanisms underlying this interplay in response to transcription-blocking DNA lesions remain largely unexplored. Here, we show that stalling of RNA polymerase II (RNAPII) at such lesions induces local chromatin acetylation, mediated primarily by the histone acetyltransferase p300. The resulting chromatin relaxation stimulates the dissociation of mature co-transcriptional spliceosomes from nascent RNA and promotes RNA:DNA hybrid (R-loop) formation, leading to ATM activation. In turn, activated ATM modulates chromatin conformation by phosphorylating histone H2A.X and triggering p38MAPK/MSK1-dependent histone H3S10 phosphorylation. Our findings highlight the cross-regulation between chromatin state and ATM signalling as a key component of the cellular response to transcription stress.
Cells, which lacked the activity of the nuclease Artemis, retained approximately 10% of unrepaired double strand breaks (DSBs) at later timepoints after ionizing radiation. Ionizing radiation induced hyperphosphorylation of Artemis mainly by ATM and in ATM deficient cells to a minor extent by DNA PK. After induction of DSBs with modified ends by a high dose of calicheamicin gamma1, Artemis was phosphorylated by DNA PK. The type of calicheamicin gamma1-induced DSBs is likely to represent a subclass of DSBs induced by ionizing radiation. DNA PK-dependent phosphorylation of Artemis after treatment with DSB inducing agents increased the cellular retention of Artemis, maintained its interaction with DNA ends and activated its endonucleolytic activity. The following model is suggested: ATM-dependent phosphorylation of Artemis after ionizing radiation could prevent DNA PK-dependent phosphorylation and activation of undesired endonucleolytic activity at DSBs, which do not require endonucleolytic processing by Artemis. The Artemis:DNA PK complex could be involved in the repair of DSBs, which carry modified ends and are refractory to repair by otherwise lesion specific enzymes because of the presence of an inhibitory lesion in the opposite strand.
B-cell chronic lymphocytic leukemia (B-CLL) is the most common B-cell leukemia among older populations in Western countries. The clinical course of B-CLL is heterogeneous: in some patients the disease course is indolent, in others it is aggressive. The B-CLL subgroups with chromosome 11q23 deletion have been associated with aggressive disease course involving ATM deletion, extensive bulky lymphadenopathy (BLA), and inferior clinical outcome. Using real-time reverse transcriptase-polymerase chain reaction, we found that ATM was consistently underexpressed in B-CLL patients with BLA, irrespective of 11q23 deletion status. In addition, B-CLL patients who presented with BLA had a significantly shorter time to treatment (2 months) than did patients without BLA (74 months). Moreover, gene expression analysis in B-CLL patients with and without BLA revealed differences in expression for genes involved in apoptosis, cell cycle, and cell adhesion. These results indicate an association between BLA and reduced expression of ATM, suggesting a role for ATM in disease progression in B-CLL.