FBH1 mediates DNA double strand breakage and apoptosis in response to DNA replication stress

• Autores: Jeong, Yeon Tae; Rossi, Mario; Cermak, Lukas; Saraf, Anita; Florens, Laurence; Washburn, Michael P.; Sung, Patrick; Schildkraut, Carl; Pagano, Michele
• Año de publicación: 2013
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Ubiquitin; Replication; Hydroxyurea; replication protein A
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular singlestranded DNA (ssDNA)?binding protein complex. Compared with control cells, FBH1-depleted cells responded to replication stress with considerably fewer double-strand breaks (DSBs), a dramatic reduction in the activation of
ATM and DNA-PK and phosphorylation of RPA2 and p53, and a significantly increased rate of survival. A minor decrease in ssDNA levels was also observed. All these phenotypes were rescued by wild-type FBH1, but not a FBH1 mutant lacking helicase activity. FBH1 depletion had no effect on other forms of genotoxic stress in which DSBs form by means that do not require ssDNA intermediates. In response to catastrophic genotoxic stress,  apoptosis prevents the persistence and propagation of DNA lesions. Our findings show that FBH1 helicase activity is required for the efficient induction of DSBs and apoptosis specifically in response to DNA replication stress.
Fil: Jeong, Yeon Tae. University Of New York; Estados Unidos
Fil: Rossi, Mario. University Of New York; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires; Argentina
Fil: Cermak, Lukas. University Of New York; Estados Unidos. Howard Hughes Medical Institute; Estados Unidos
Fil: Saraf, Anita. The Stowers Institute for Medical Research; Estados Unidos
Fil: Florens, Laurence. The Stowers Institute for Medical Research; Estados Unidos
Fil: Washburn, Michael P.. The Stowers Institute for Medical Research; Estados Unidos. University of Kansas; Estados Unidos
Fil: Sung, Patrick. University Of Yale; Estados Unidos
Fil: Schildkraut, Carl. Albert Einstein College of Medicine; Estados Unidos
Fil: Pagano, Michele. University Of New York; Estados Unidos. Howard Hughes Medical Institute; Estados Unidos