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CtIP/Ctp1/Sae2, molecular form fit for function
Institution:2. Hospital General de Alicante, Alicante, Spain;3. Hospital Sant Pau i la Santa Creu, Barcelona, Spain;4. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain;5. Oncology Institute of Southern Switzerland, Locarno, Switzerland;1. Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA;2. Department of Therapeutic Radiobiology, Yale University School of Medicine, New Haven, CT 06520, USA;1. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA;2. Department of Molecular Genetics, Erasmus University Medical Center, 3000 Rotterdam, the Netherlands;3. Department of Radiation Oncology, Erasmus University Medical Center, 3000 Rotterdam, the Netherlands;4. Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland;1. Institute for Cancer Genetics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA;2. Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA;3. Department of Genetics and Development, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
Abstract:Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By modulating the nucleolytic 5′-3′ resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities. CtIP homologs are largely intrinsically unstructured proteins comprised of expanded regions of low complexity sequence, rather than defined folded domains typical of DNA damage metabolizing enzymes and nucleases. A compact structurally conserved N-terminus forms a functionally critical tetrameric helical dimer of dimers (THDD) region that bridges CtIP oligomers, and is flexibly appended to a conserved C-terminal Sae2-homology DNA binding and DSB repair pathway choice regulatory hub which influences nucleolytic activities of the MRN core nuclease complex. The emerging evidence from structural, biophysical, and biological studies converges on CtIP having functional roles in DSB repair that include: 1) dynamic DNA strand coordination through direct DNA binding and DNA bridging activities, 2) MRN nuclease complex cofactor functions that direct MRN endonucleolytic cleavage of protein-blocked DSB ends and 3) acting as a protein binding hub targeted by the cell cycle regulatory apparatus, which influences CtIP expression and activity via layers of post-translational modifications, protein–protein interactions and DNA binding.
Keywords:CtIP/Ctp1/Sae2  Homologous recombination  Resection  DNA bridging  Intrinsically disordered proteins
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