title: 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.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: S S
authors.initials: SS
authors.lastname: Kharat
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: V
authors.initials: V
authors.lastname: Tripathi
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: A P
authors.initials: AP
authors.lastname: Damodaran
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: R
authors.initials: R
authors.lastname: Priyadarshini
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Chandra
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: S
authors.identifier: http://orcid.org/0000-0001-5850-8075
authors.initials: S
authors.lastname: Tikoo
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: R
authors.initials: R
authors.lastname: Nandhakumar
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: V
authors.initials: V
authors.lastname: Srivastava
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Priya
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: M
authors.initials: M
authors.lastname: Hussain
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Kaur
authors.affiliation: 21st Century Biochemicals, 260 Cedar Hill Street, Marlboro, MA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Fishman
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: S
authors.identifier: http://orcid.org/0000-0002-6365-1770
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D043171:Chromosomal Instability; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D008938:Mitosis; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D053484:RecQ Helicases / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D013912:Threonine; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C097151:Bloom syndrome protein; D053484:RecQ Helicases