- Email: [email protected]
Chromatin component identified as tumour suppressor
Newsdesk Is a European Research Council now on the EU’s agenda? Debates surrounding the establishment of a European Research Council (ERC) have advanced from “Why an ERC?” to how best to launch a pan-European entity to support investigator-driven, fundamental research in scientific endeavors ranging from the life sciences to particle physics. “The fact that the ERC has become a political animal is very good for the idea, the concept, and the possibility of its establishment”, says Enric Banda of the European Science Foundation (ESF), Strasbourg, France. Several expert groups are addressing issues related to the “how-tos” of an ERC. “Do you have a big bang, in which you start everything [from] astronomy to zoology at the same time, or do you have a step-wise, phased-in startup?” asks Frank Gannon of the
European Molecular Biology Organisation (EMBO) and European Molecular Biology Conference (EMBC), Heidelberg, Germany. Scientists and policy officials are considering the possibility of an ERC that would, from its beginning, cover all scientific disciplines, as suggested in the report of the ESF High-Level Working Group in April 2003. Also under discussion are prototypical options offered by subject-specific groups such as EMBO, which recently expanded its activities to include a Research Award Programme. This new programme reflects an increase, via the EMBC, in Europeanwide funding of research that is investigator-initiated and selected on the basis of quality. Therefore, it offers a model of a discipline-specific
academy that may well have both the expertise and practical experience to serve as a prototype. As described by Luc Van Dyck of the European Life Science Forum, Heidelberg, Germany, creation of a pilot program within such a group could precede the step-wise establishment of others, possibly within a broad-based organization such as the ESF (EMBO reports 2003; 4: 544–46). “I quite agree with a step-wise approach”, responds Banda. “But it is one which slowly introduces mechanisms for funding across disciplines”. The hope is that establishment of an ERC will appear on the agenda of the European Union’s Council of Ministers when Ireland assumes presidency of the EU in January, 2004. Mary Weideman
Chromatin component identified as tumour suppressor
Courtesy of S Difilippantonio, M Difilippantonio, and A. Nussenzweig
A protein component of chromatin, histone H2AX, is a In 2002, both groups derived mice null for H2AX. dose-dependent tumour suppressor, say US researchers. “Somewhat unexpectedly, these mice were viable”, says Two teams, headed by André Nussenzweig (National Cancer Nussenzweig, “although their chromosomes contained Institute, MD, USA) and Frederick Alt (The Children’s many breaks and translocations.” This genomic instability, Hospital, MA, USA), independently report that loss of a he continues, did not result in tumour development because single allele of H2AX in p53 null mice causes genomic other cellular systems, in particular the p53 pathway, instability and the development of several types of tumour detected the DNA damage and caused cell-cycle arrest, (Cell 2003; 114: 359–70; 371–83). apoptosis or both. The gene for human H2AX lies at The researchers have now found 11q23, a chromosomal region often that, in the absence of p53, knocking altered in human tumours, and both out one or both copies of H2AX leads teams are now investigating whether to tumour formation. Their conchanges in H2AX are involved in clusion is that H2AX modulates DSB human cancer. A positive answer, says repair. These results are interesting, Steve Jackson (University of Camcomments Jackson, “because they bridge, UK), could have implications show that a chromatin structural for assessing cancer predisposition and component can act as a tumour in deciding which patients will respond suppressor”. However, he notes, best to radiotherapy. “H2AX is not behaving like a classical Genomic instability is a charactertumour suppressor because tumours istic feature of tumours. Central to a arising in heterozygous animals have cell’s ability to maintain its genomic not lost the wild-type allele”. stability are systems that repair DNA Exactly how H2AX modulates Absence of H2AX and p53 leads to double-strand breaks (DSBs). This type chromosome translocations. DNA repair is unclear, but of DNA lesion is caused by exogenous Nussenzweig and Alt speculate that agents such as radiation, but also occurs during DNA H2AX phosphorylation in response to a DSB could change replication and during processes such as the gene the chromatin structure around the break. This might help rearrangements that occur in lymphocyte development. One to keep the broken DNA ends together, says Nussenzweig, of the earliest events in DSB repair is H2AX phosphorylation or it could ensure proper assembly of the other DNA repair in the chromatin flanking the break, explains Nussenzweig. factors. “The density of H2AX in the chromatin could be This and other data suggest that H2AX is involved in sensing crucial for processes like this”, suggests Alt. Jane Bradbury or processing DNA DSBs, adds Alt.
522
THE LANCET Oncology Vol 4 September 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
European Molecular Biology Organisation (EMBO) and European Molecular Biology Conference (EMBC), Heidelberg, Germany. Scientists and policy officials are considering the possibility of an ERC that would, from its beginning, cover all scientific disciplines, as suggested in the report of the ESF High-Level Working Group in April 2003. Also under discussion are prototypical options offered by subject-specific groups such as EMBO, which recently expanded its activities to include a Research Award Programme. This new programme reflects an increase, via the EMBC, in Europeanwide funding of research that is investigator-initiated and selected on the basis of quality. Therefore, it offers a model of a discipline-specific
academy that may well have both the expertise and practical experience to serve as a prototype. As described by Luc Van Dyck of the European Life Science Forum, Heidelberg, Germany, creation of a pilot program within such a group could precede the step-wise establishment of others, possibly within a broad-based organization such as the ESF (EMBO reports 2003; 4: 544–46). “I quite agree with a step-wise approach”, responds Banda. “But it is one which slowly introduces mechanisms for funding across disciplines”. The hope is that establishment of an ERC will appear on the agenda of the European Union’s Council of Ministers when Ireland assumes presidency of the EU in January, 2004. Mary Weideman
Chromatin component identified as tumour suppressor
Courtesy of S Difilippantonio, M Difilippantonio, and A. Nussenzweig
A protein component of chromatin, histone H2AX, is a In 2002, both groups derived mice null for H2AX. dose-dependent tumour suppressor, say US researchers. “Somewhat unexpectedly, these mice were viable”, says Two teams, headed by André Nussenzweig (National Cancer Nussenzweig, “although their chromosomes contained Institute, MD, USA) and Frederick Alt (The Children’s many breaks and translocations.” This genomic instability, Hospital, MA, USA), independently report that loss of a he continues, did not result in tumour development because single allele of H2AX in p53 null mice causes genomic other cellular systems, in particular the p53 pathway, instability and the development of several types of tumour detected the DNA damage and caused cell-cycle arrest, (Cell 2003; 114: 359–70; 371–83). apoptosis or both. The gene for human H2AX lies at The researchers have now found 11q23, a chromosomal region often that, in the absence of p53, knocking altered in human tumours, and both out one or both copies of H2AX leads teams are now investigating whether to tumour formation. Their conchanges in H2AX are involved in clusion is that H2AX modulates DSB human cancer. A positive answer, says repair. These results are interesting, Steve Jackson (University of Camcomments Jackson, “because they bridge, UK), could have implications show that a chromatin structural for assessing cancer predisposition and component can act as a tumour in deciding which patients will respond suppressor”. However, he notes, best to radiotherapy. “H2AX is not behaving like a classical Genomic instability is a charactertumour suppressor because tumours istic feature of tumours. Central to a arising in heterozygous animals have cell’s ability to maintain its genomic not lost the wild-type allele”. stability are systems that repair DNA Exactly how H2AX modulates Absence of H2AX and p53 leads to double-strand breaks (DSBs). This type chromosome translocations. DNA repair is unclear, but of DNA lesion is caused by exogenous Nussenzweig and Alt speculate that agents such as radiation, but also occurs during DNA H2AX phosphorylation in response to a DSB could change replication and during processes such as the gene the chromatin structure around the break. This might help rearrangements that occur in lymphocyte development. One to keep the broken DNA ends together, says Nussenzweig, of the earliest events in DSB repair is H2AX phosphorylation or it could ensure proper assembly of the other DNA repair in the chromatin flanking the break, explains Nussenzweig. factors. “The density of H2AX in the chromatin could be This and other data suggest that H2AX is involved in sensing crucial for processes like this”, suggests Alt. Jane Bradbury or processing DNA DSBs, adds Alt.
522
THE LANCET Oncology Vol 4 September 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.