Abstract
The cellular response to DNA damage (DDR) that causes replication collapse and/or DNA double strand breaks, is characterised by a massive change in the post-translational modifications (PTM) of hundreds of proteins involved in the detection and repair of DNA damage, and the communication of the state of damage to the cellular systems that regulate replication and cell division. A substantial proportion of these PTMs involve targeted phosphorylation, which among other effects, promotes the formation of multiprotein complexes through the specific binding of phosphorylated motifs on one protein, by specialised domains on other proteins. Understanding the nature of these phosphorylation mediated interactions allows definition of the pathways and networks that coordinate the DDR, and helps identify new targets for therapeutic intervention that may be of benefit in the treatment of cancer, where DDR plays a key role. In this review we summarise the present understanding of how phosphorylated motifs are recognised by BRCT domains, which occur in many DDR proteins. We particularly focus on TOPBP1 – a multi-BRCT domain scaffold protein with essential roles in replication and the repair and signalling of DNA damage.
Highlights
The DNA Damage Response (DDR) is an extraordinary, transient reconfiguring of cellular behaviour, driven by a massive cascade of post-translational events downstream of DNA damage detection
In particular we focus on the function of BRCA1 o C-terminus (BRCT) domains in recognition of phosphorylated motifs in DDR proteins, and r the role of DNA topoisomerase II binding protein 1 (TOPBP1) – a large scaffold protein p containing multiple BRCT domains - that plays key roles in regulating replication, DNA break - repair and mitosis
All the multi-BRCT modules of TOPBP1 have been implicated in binding to multiple ligands, and no direct ligands of BRCT0 or the singleton BRCT domains 3 and 6 have yet been definitively identified, there is no reason to assume that these will be different
Summary
The DNA Damage Response (DDR) is an extraordinary, transient reconfiguring of cellular behaviour, driven by a massive cascade of post-translational events (primarily phosphorylation) downstream of DNA damage detection. Subsequent studies demonstrated that γH2AX is a direct participant in recruitment of repair factors, and interacts directly with MDC1 [7]; via specific binding of its C-terminal tetrapeptide incorporating pSer139, to the tandem BRCT domain at the C-terminus of MDC1 [8] (FIGURE 1A). While the C-terminal BRCT2 modules of MDC1, 53BP1, PTIP and MCPH1 all appear to be adapted for unique recognition of the highly acidic terminal phosphorylated-motif of γH2AX, the structurally homologous BRCT2 module at the C-terminus of BRCA1 is able interact more promiscuously with phosphorylation sites embedded within their ligand proteins’ amino acid sequence, that incorporate a pSer-X-X-Phe motif [32]. Other phospho-dependant ligands of BRCA1-BRCT2 are likely to be identified
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