Poster Presentation 27th Lorne Cancer Conference 2015

K63-linked ubiquitylation of BLM is required for its recruitment to the sites of DNA damage to suppress homologous recombination (#282)

Shweta Tikoo 1 2 3 , Vinoth Madhavan 3 , Mansoor Hussain 3 , Edward Miller 4 , Prateek Arora 3 , Anastasia Zlatanou 4 , Priyanka Modi 3 , Kelly Townsend 4 , Grant Stewart 4 , Sagar Sengupta 3
  1. Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, NSW, Australia
  2. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  3. Signal Transduction Lab-2, National Institute of Immunology, New Delhi, India
  4. School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom

BLM Syndrome patients exhibit the widest known spectrum of cancers known in single patients. BLM Syndrome is caused by mutations in BLM helicase, which is a caretaker tumour suppressor involved in regulating homologous recombination post genotoxic stress. Though much is known about the downstream processes of BLM, the mechanisms involved in its recruitment to the sites of damage post genotoxic stress are not very well established. We demonstrate that Ubc13/RNF8 mediated K63-linked ubiquitylation of BLM is essential for its recruitment from its known storage depot “PML Bodies” to the sites of DNA damage and the abrogation of this machinery leads to an increase in the levels of homologous recombination. We provide unequivocal evidence that BLM physically interacts with the members of the ubiquitylation machinery and with RAP80, a protein that is essential for the recruitment of BRCA1 to the sites of DNA damage. We thus establish that K63-linked ubiquitylation of BLM is essential to limit the levels of HR, which is crucial for maintaining genomic integrity.

  1. Tikoo S, Madhavan V, Hussain M, Miller ES, Arora P, Zlatanou A, Modi P, Townsend K, Stewart GS, Sengupta S. (2013) Ubiquitin-dependent recruitment of the Bloom Syndrome helicase in response to replication stress is required to suppress homologous recombination. EMBO J. 32(12): 1778-1792.
  2. Tikoo S, Sengupta S. (2010) Time to Bloom. Genome Integr. 1(1): 14.