Mitotic phosphorylation of Bloom helicase at Thr182 is required for its proteasomal degradation and maintenance of chromosomal stability.

Abstract

Mutations in Bloom helicase (BLM) lead to Bloom Syndrome (BS). BS is characterized by multiple clinical manifestations including predisposition to a wide spectrum of cancers. Studies have revealed the mechanism of BLM recruitment after stalled replication and its role during the repair of DNA damage. We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. Consequently lack of Thr182 phosphorylation leads to multiple manifestations of chromosomal instability including increased levels of DNA damage, lagging chromatin, micronuclei formation, breaks and quadriradials. Hence Thr182 phosphorylation on BLM has two functions-it regulates BLM turnover during mitosis and also helps to maintain the chromosomal stability.

• Authors: S S Kharat, V Tripathi, A P Damodaran, R Priyadarshini, S Chandra, S Tikoo, R Nandhakumar, V Srivastava, S Priya, M Hussain, S Kaur, J B Fishman, S Sengupta
• Journal: Oncogene (Oncogene) Vol. 35 Issue 8 Pg. 1025-38 (Feb 25 2016) ISSN: 1476-5594 [Electronic] England
• PMID: 26028025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• F-Box Proteins
• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• Threonine
• Ubiquitin-Protein Ligases
• Proteasome Endopeptidase Complex
• Bloom syndrome protein
• RecQ Helicases

Topics

• Cell Cycle Proteins (metabolism)
• Cell Line
• Chromosomal Instability
• F-Box Proteins (metabolism)
• F-Box-WD Repeat-Containing Protein 7
• Humans
• Mitosis
• Phosphorylation
• Proteasome Endopeptidase Complex (metabolism)
• RecQ Helicases (metabolism)
• Threonine (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination