Dynamics of DNA repair suggested by the subcellular localization of Brca1 and Brca2 proteins.
The localization of proteins to specific subcellular compartments often reveals clues regarding their biological functions. Although significant progress has been made towards understanding how damaged DNA is repaired, experiments to date have primarily focused on signal transduction pathways that activate DNA repair protein complexes and on how these complexes are assembled. Current evidence suggests that certain DNA repair processes are spatially organized such that aberrant DNA structures can be brought into proximity with DNA repair proteins at fixed sites. Since biochemical evidence suggests that the tumor suppressor proteins, Brca1 and Brca2, may mediate the assembly of protein complexes involved in the repair of damaged DNA, we have performed subcellular fractionation experiments to determine the subnuclear localization of these proteins. The majority of Brca1 and Brca2 proteins were found to interact tightly with the nuclear matrix. Furthermore, within the limits of detection, localization of Brca1 and Brca2 to the nuclear matrix was not altered following treatment of cells with DNA damaging agents that activate homology-mediated double-stranded DNA break and transcription-coupled repair pathways. Our findings suggest that Brca1 and Brca2 may perform their DNA repair-related functions from positions that are anchored to the nuclear matrix. These data are consistent with proposed models that suggest that components of specific repair complexes residing on the nuclear matrix function to recruit damaged DNA.
Huber
L Julie
LJ
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
Chodosh
Lewis A
LA
D000818:Animals; D019313:BRCA1 Protein / Q000276:immunology / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism*; D002460:Cell Line; D004260:DNA Repair / Q000502:physiology*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007211:Indoles; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D015530:Nuclear Matrix / Q000378:metabolism*
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D007211:Indoles; C007293:DAPI