Disruption of BRCA1 function results in telomere lengthening and increased anaphase bridge formation in immortalized cell lines.
BRCA1 is a tumor suppressor that functions in controlling cell growth and maintaining genomic stability. BRCA1 has also been implicated in telomere maintenance through its ability to regulate the transcription of hTERT, the catalytic subunit of telomerase, resulting in telomere shortening, and to colocalize with the telomere-binding protein TRF1. The high incidence of nonreciprocal translocations in tumors arising from BRCA1 mutation carriers and Brca1-null mice also raises the possibility that BRCA1 plays a role in telomere protection. To date, however, the consequences for telomere status of disrupting BRCA1 have not been reported. To examine the role of BRCA1 in telomere regulation, we have expressed a dominant-negative mutant of BRCA1 (trBRCA1), known to disrupt multiple functions of BRCA1, in telomerase-positive mammary epithelial cells (SVCT) and telomerase-negative ALT cells (GM847). In SVCT cells, expression of trBRCA1 resulted in an increased incidence of anaphase bridges and in an increase in telomere length, but no change in telomerase activity. In GM847 cells, trBRCA1 also increased anaphase bridge formation but did not induce any change in telomere length. BRCA1 colocalized with TRF2 in telomerase-positive cells and with a small subset of ALT-associated PML bodies (APBs) in ALT cells. Together, these results raise the possibility that BRCA1 could play a role in telomere protection and suggest a potential mechanism for one of the phenotypes of BRCA1-deficient cells.
French
Juliet D
JD
School of Molecular and Microbial Sciences, University of Queensland, St. Lucia, Queensland, Australia.
Dunn
Jasmyn
J
Smart
Chanel E
CE
Manning
Nathan
N
Brown
Melissa A
MA
D000705:Anaphase / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D019398:Genes, BRCA1 / Q000502:physiology*; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000502:physiology*; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D019098:Telomerase