Mechanistic insights into the recognition of 5-methylcytosine oxidation derivatives by the SUVH5 SRA domain

Rajakumara, Eerappa; Nakarakanti, Naveen Kumar; Nivya, M. Angel; Satish, Mutyala

doi:10.1038/srep20161

Mechanistic insights into the recognition of 5-methylcytosine oxidation derivatives by the SUVH5 SRA domain

Journal Article · Thu Feb 04 00:00:00 EST 2016 · Scientific Reports

DOI:https://doi.org/10.1038/srep20161· OSTI ID:1624817

Rajakumara, Eerappa ^[1]; Nakarakanti, Naveen Kumar ^[2]; Nivya, M. Angel ^[2]; Satish, Mutyala ^[2]

Indian Inst. of Technology (IIT), Telangana (India). Dept. of Biotechnology; DOE/OSTI
Indian Inst. of Technology (IIT), Telangana (India). Dept. of Biotechnology

5-Methylcytosine (5 mC) is associated with epigenetic gene silencing in mammals and plants. 5 mC is consecutively oxidized to 5-hydroxymethylcytosine (5 hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by ten-eleven translocation enzymes. We performed binding and structural studies to investigate the molecular basis of the recognition of the 5 mC oxidation derivatives in the context of a CG sequence by the SET- and RING-associated domain (SRA) of the SUVH5 protein (SUVH5 SRA). Using calorimetric measurements, we demonstrate that the SRA domain binds to the hydroxymethylated CG (5hmCG) DNA duplex in a similar manner to methylated CG (5mCG). Interestingly, the SUVH5 SRA domain exhibits weaker affinity towards carboxylated CG (5caCG) and formylated CG (5fCG). We report the 2.6 Å resolution crystal structure of the SUVH5 SRA domain in a complex with fully hydroxymethyl-CG and demonstrate a dual flip-out mechanism, whereby the symmetrical 5hmCs are simultaneously extruded from the partner strands of the DNA duplex and are positioned within the binding pockets of individual SRA domains. The hydroxyl group of 5hmC establishes both intra- and intermolecular interactions in the binding pocket. Collectively, we show that SUVH5 SRA recognizes 5hmC in a similar manner to 5 mC, but exhibits weaker affinity towards 5 hmC oxidation derivatives.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States); Indian Inst. of Technology, Telangana (India)

Sponsoring Organization:: Government of India; USDOE Office of Science (SC), Engineering & Technology. Office of Accelerator R&D and Production

Grant/Contract Number:: SC0012704

OSTI ID:: 1624817

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 6; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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The finger loop of the SRA domain in the E3 ligase UHRF1 is a regulator of ubiquitin targeting and is required for the maintenance of DNA methylation Vaughan, Robert M.; Rothbart, Scott B.; Dickson, Bradley M. Journal of Biological Chemistry, Vol. 294, Issue 43 https://doi.org/10.1074/jbc.ra119.010160	journal	September 2019
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