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The bloom syndrome protein, BLM, inhibits homologous recombination by disrupting RAD51 nucleoprotein filaments
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Patel, Dharm S.. The bloom syndrome protein, BLM, inhibits homologous recombination by disrupting RAD51 nucleoprotein filaments. Retrieved from https://doi.org/doi:10.7282/T3280BRG

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TitleThe bloom syndrome protein, BLM, inhibits homologous recombination by disrupting RAD51 nucleoprotein filaments
NamePatel, Dharm S. (author); Bunting, Samuel F (chair); Brill, Steven J (internal member); Anderson, Stephen (internal member); Ganesan, Shridar (outside member); Rutgers University; School of Graduate Studies
Date Created2017
Other Date2017-10 (degree)
SubjectBiochemistry, DNA repair, BRCA genes
Extent1 online resource (xii, 128 p. : ill.)
DescriptionBRCA1-deficient cells exhibit increased genomic instability following DNA damaging treatments due to a defect in the homologous recombination (HR) DNA repair pathway. Here, we show that the Bloom Syndrome Protein, BLM, mediates the genomic instability observed in BRCA1-deficient cells by a mechanism that depends in part on its anti- recombinogenic activity. Ablation of BLM in BRCA1-deficient cells allows the HR repair pathway to be restored, leading to a partial rescue of the genomic instability and replication fork degradation that is present in BRCA1-deficient cells. The stable accumulation of RAD51 at DNA double-strand break sites is inhibited by BLM in BRCA1-deficient B cells. However, DNA end resection is not impacted by single or co- deletion of BRCA1 and BLM. Furthermore, cells co-deficient in BRCA1 and BLM display limited sensitivity to PARP inhibition. The rescue in HR and PARPi sensitivity phenotypes following deletion of BLM is only present in hypomorphic Brca1Δ11/Δ11 cells, and not in the RING domain deficient Brca1Δ2/Δ2 or nullizygous cells. Importantly, the helicase activity of BLM is required for its anti-recombinogenic function. Lastly, we demonstrate that BLM belongs to a class of anti-recombinases that limit the rate of HR. These results demonstrate that the anti-recombinogenic activity of BLM is of potentially great significance for regulating the balance of HR versus other error-prone repair pathways.
NotePh.D.
NoteIncludes bibliographical references
Noteby Dharm S. Patel
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3280BRG
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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