Structural highlights
Function
[RAD4_SCHPO] Essential component for DNA replication and also the checkpoint control system which couples S and M phases. May directly or indirectly interact with chromatin proteins to form the complex required for the initiation and/or progression of DNA synthesis. [SLD3_SCHPO] Required for loading and maintenance of stable association of cdc45 with chromatin during initiation and elongation of DNA replication. Also involved in temporal regulation of origin firing. Plays a role in meiosis.[1] [2]
Publication Abstract from PubMed
TOPBP1 and its fission yeast homologueRad4, are critical players in a range of DNA replication, repair and damage signalling processes. They are composed of multiple BRCT domains, some of which bind phosphorylated motifs in other proteins. They thus act as multi-point adaptors bringing proteins together into functional combinations, dependent on post-translational modifications downstream of cell cycle and DNA damage signals. We have now structurally and/or biochemically characterised a sufficient number of high-affinity complexes for the conserved N-terminal region of TOPBP1 and Rad4 with diverse phospho-ligands, including human RAD9 and Treslin, and Schizosaccharomyces pombe Crb2 and Sld3, to define the determinants of BRCT domain specificity. We use this to identify and characterise previously unknown phosphorylation-dependent TOPBP1/Rad4-binding motifs in human RHNO1 and the fission yeast homologue of MDC1, Mdb1. These results provide important insights into how multiple BRCT domains within TOPBP1/Rad4 achieve selective and combinatorial binding of their multiple partner proteins.
BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands.,Day M, Rappas M, Ptasinska K, Boos D, Oliver AW, Pearl LH Elife. 2018 Oct 8;7. pii: 39979. doi: 10.7554/eLife.39979. PMID:30295604[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nakajima R, Masukata H. SpSld3 is required for loading and maintenance of SpCdc45 on chromatin in DNA replication in fission yeast. Mol Biol Cell. 2002 May;13(5):1462-72. PMID:12006645 doi:http://dx.doi.org/10.1091/mbc.02-01-0006
- ↑ Martin-Castellanos C, Blanco M, Rozalen AE, Perez-Hidalgo L, Garcia AI, Conde F, Mata J, Ellermeier C, Davis L, San-Segundo P, Smith GR, Moreno S. A large-scale screen in S. pombe identifies seven novel genes required for critical meiotic events. Curr Biol. 2005 Nov 22;15(22):2056-62. PMID:16303567 doi:http://dx.doi.org/S0960-9822(05)01277-7
- ↑ Day M, Rappas M, Ptasinska K, Boos D, Oliver AW, Pearl LH. BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands. Elife. 2018 Oct 8;7. pii: 39979. doi: 10.7554/eLife.39979. PMID:30295604 doi:http://dx.doi.org/10.7554/eLife.39979
