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At least 811 records · Page 45Linked to original sources
PubMed1998

ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins.

The p53 tumour-suppressor protein is a sequence-specific DNA-binding transcription factor that induces cell cycle arrest or apoptosis in response to genotoxic stress. Activation of p53 by DNA-damaging agents is critical for eliminating cells with damaged genomic DNA and underlies the apoptotic response of human cancers treated with ionizing radiation (IR) and radiomimetic drugs. The molecular mechanisms by which DNA damage activates p53 have not been elucidated. Both the levels of p53 protein and its affinity for specific DNA sequences increase in response to genotoxic stress. In vitro, the affinity of p53 for DNA is regulated by its carboxy-terminus. We therefore examined whether this region of p53 is targeted by DNA-damage signalling pathways in vivo. In nonirradiated cells, serines 376 and 378 of p53 were phosphorylated. IR led to dephosphorylation of Ser376, creating a consensus binding site for 14-3-3 proteins and leading to association of p53 with 14-3-3. In turn, this increased the affinity of p53 for sequence-specific DNA. Consistent with the lack of p53 activation by IR in ataxia telangiectasia (AT; refs 14,15), neither Ser376 dephosphorylation, nor the interaction of p53 with 14-3-3 proteins occurred in AT cells.

14-3-3 Proteins↗
PubMed2005

Phosphorylation of Chk1 by ATM- and Rad3-related (ATR) in Xenopus egg extracts requires binding of ATRIP to ATR but not the stable DNA-binding or coiled-coil domains of ATRIP.

ATR, a critical regulator of DNA replication and damage checkpoint responses, possesses a binding partner called ATRIP. We have studied the functional properties of Xenopus ATR and ATRIP in incubations with purified components and in frog egg extracts. In purified systems, ATRIP associates with DNA in both RPA-dependent and RPA-independent manners, depending on the composition of the template. However, in egg extracts, only the RPA-dependent mode of binding to DNA can be detected. ATRIP adopts an oligomeric state in egg extracts that depends upon binding to ATR. In addition, ATR and ATRIP are mutually dependent on one another for stable binding to DNA in egg extracts. The ATR-dependent oligomerization of ATRIP does not require an intact coiled-coil domain in ATRIP and does not change in the presence of checkpoint-inducing DNA templates. Egg extracts containing a mutant of ATRIP that cannot bind to ATR are defective in the phosphorylation of Chk1. However, extracts containing mutants of ATRIP lacking stable DNA-binding and coiled-coil domains show no reduction in the phosphorylation of Chk1 in response to defined DNA templates. Furthermore, activation of Chk1 does not depend upon RPA under these conditions. These results suggest that ATRIP must associate with ATR in order for ATR to carry out the phosphorylation of Chk1 effectively. However, this function of ATRIP does not involve its ability to mediate the stable binding of ATR to defined checkpoint-inducing DNA templates in egg extracts, does not require an intact coiled-coil domain, and does not depend on RPA.

Animals↗
PubMed2006

Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation.

Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes initiated by activation-induced cytidine deaminase. Here, we have studied the role of ataxia telangiectasia and Rad3-related protein (ATR) in CSR by analyzing the recombinational junctions, resulting from in vivo switching, in cells from patients with mutations in the ATR gene. The proportion of cells that have switched to immunoglobulin (Ig)A and IgG in the peripheral blood seems to be normal in ATR-deficient (ATRD) patients and the recombined S regions show a normal "blunt end-joining," but impaired end joining with partially complementary (1-3 bp) DNA ends. There was also an increased usage of microhomology at the mu-alpha switch junctions, but only up to 9 bp, suggesting that the end-joining pathway requiring longer microhomologies (> or =10 bp) may be ATR dependent. The SHM pattern in the Ig variable heavy chain genes is altered, with fewer mutations occurring at A and more mutations at T residues and thus a loss of strand bias in targeting A/T pairs within certain hotspots. These data suggest that the role of ATR is partially overlapping with that of ataxia telangiectasia-mutated protein, but that the former is also endowed with unique functional properties in the repair processes during CSR and SHM.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1997

ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase.

Telomere loss has been proposed as a mechanism for counting cell divisions during aging in normal somatic cells. How such a mitotic clock initiates the intracellular signalling events that culminate in G1 cell cycle arrest and senescence to restrict the lifespan of normal human cells is not known. We investigated the possibility that critically short telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells. We show that the DNA binding and transcriptional activity of p53 protein increases with cell age in the absence of any marked increase in the level of p53 protein, and that p21(WAF1) promoter activity in senescent cells is dependent on both p53 and the transcriptional co-activator p300. Moreover, we detected increased specific activity of p53 protein in AT fibroblasts, which exhibit accelerated telomere loss and undergo premature senescence, compared with normal fibroblasts. We investigated the possibility that poly(ADP-ribose) polymerase is involved in the post-translational activation of p53 protein in aging cells. We show that p53 protein can associate with PARP and inhibition of PARP activity leads to abrogation of p21 and mdm2 expression in response to DNA damage. Moreover, inhibition of PARP activity leads to extension of cellular lifespan. In contrast, hyperoxia, an activator of PARP, is associated with accelerated telomere loss, activation of p53 and premature senescence. We propose that p53 is post-translationally activated not only in response to DNA damage but also in response to the critical shortening of telomeres that occurs during cellular aging.

Alleles↗