Breaks invisible to the DNA damage response machinery accumulate in ATM-deficient cells
Martín Flix, Marta (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Terradas, Mariona (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Iliakis, George (University Duisburg-Essen Medical School)
Tusell Padrós, Laura (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Genescà, Anna (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")

Fecha:	2009
Resumen:	After irradiation, ATM defective cells accumulate unrepaired double strand breaks (DSBs) for several cell divisions. At the chromosome level, unresolved DSBs appear as chromosome breaks that can be efficiently scored by using telomeric and mFISH probes. H2AX is immediately activated by ATM in response to DNA damage and its phosphorylated form, γH2AX, flanks the DSB through several megabases. The γH2AX-labeling status of broken chromosome ends was analyzed in AT cells to check whether the DNA damage response was accurately taking place in these persistent DSBs. The results show that one quarter of the scored breaks are devoid of γH2AX foci in metaphase spreads from ATM-deficient cells, and this fraction is significantly higher than in normal cells (χ2 < 0. 05). Accumulation of sensor and repair proteins at damaged sites is a key event in the cellular response to DSBs, so MRE11 labeling at broken ends was also analyzed. While all γH2AX foci scored at visible broken ends colocalize with MRE11 foci, all γH2AX-unlabeled breaks are also devoid of MRE11-labeling. The present results suggest that a significant subset of the AT long-lived DSBs may persist as " invisible" DSBs due to deficient detection by the DNA damage repair machinery. Eventually the properly signaled DSBs will be repaired while invisible breaks may indefinitely accumulate; most probably contributing to the AT cells' well known genomic instability.
Ayudas:	Ministerio de Educación y Ciencia SAF2004-20372-E Ministerio de Educación y Ciencia SAF2006-01653 Instituto de Salud Carlos III RD06/0020/1020 Agència de Gestió d'Ajuts Universitaris i de Recerca 2005/SGR-00437
Nota:	Altres ajuts: Fundació La Marató, Grant number TV32005-050110
Derechos:	Tots els drets reservats.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	ATM ; Radiosensitivity ; Chromosome breaks ; DNA damage response ; γH2AX-labelling
Publicado en:	Genes Chromosomes and Cancer, Vol. 48, Issue 9 (September 2009) , p. 745-759, ISSN 1098-2264

DOI: 10.1002/gcc.20679

Postprint 39 p, 4.0 MB

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