Structural insight into BLM recognition by TopBP1

Journal article

Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5. This interaction utilizes the same surface of BRCT5 that recognizes the DNA damage mediator, MDC1; however the binding orientations of MDC1 and BLM are reversed. While the MDC1 interactions are largely electrostatic, the interaction with BLM has higher affinity and relies on a mix of electrostatics and hydrophobicity. We suggest that similar evolutionarily conserved interactions may govern interactions between TopBP1 and 53BP1.

Authors: Sun, L; Huang, Y; Edwards, R; Yang, S; Blackford, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Structure
• Volume: 25
• Issue: 10
• Pages: 1582–1588.e3
• Publication date: 2017-09-14
• Acceptance date: 2017-08-15
• DOI: 10.1016/j.str.2017.08.005
• EISSN: 1878-4186
• ISSN: 0969-2126
• Pmid: 28919440
• Language: English
• Keywords: X-ray crystallography; Bloom syndrome; phosphopeptide interactions; fluorescence polarization; BLM; TopBP1; BRCT