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The structure of the human RNase H2 complex defines key interaction interfaces relevant to enzyme function and human disease.

Reijns MA, Bubeck D, Gibson LC, Graham SC, Baillie GS, Jones EY, Jackson AP
J Biol Chem 286 10530-9 (2011)
Related entries: 3kio, 3p56

Cited: 66 times
EuropePMC logo PMID: 21177854

Abstract

Ribonuclease H2 (RNase H2) is the major nuclear enzyme involved in the degradation of RNA/DNA hybrids and removal of ribonucleotides misincorporated in genomic DNA. Mutations in each of the three RNase H2 subunits have been implicated in a human auto-inflammatory disorder, Aicardi-Goutières Syndrome (AGS). To understand how mutations impact on RNase H2 function we determined the crystal structure of the human heterotrimer. In doing so, we correct several key regions of the previously reported murine RNase H2 atomic model and provide biochemical validation for our structural model. Our results provide new insights into how the subunits are arranged to form an enzymatically active complex. In particular, we establish that the RNASEH2A C terminus is a eukaryotic adaptation for binding the two accessory subunits, with residues within it required for enzymatic activity. This C-terminal extension interacts with the RNASEH2C C terminus and both are necessary to form a stable, enzymatically active heterotrimer. Disease mutations cluster at this interface between all three subunits, destabilizing the complex and/or impairing enzyme activity. Altogether, we locate 25 out of 29 residues mutated in AGS patients, establishing a firm basis for future investigations into disease pathogenesis and function of the RNase H2 enzyme.

Articles - 3p5j mentioned but not cited (2)

  1. The structure of the human RNase H2 complex defines key interaction interfaces relevant to enzyme function and human disease. Reijns MA, Bubeck D, Gibson LC, Graham SC, Baillie GS, Jones EY, Jackson AP. J. Biol. Chem. 286 10530-10539 (2011)
  2. A Two-Layer SVM Ensemble-Classifier to Predict Interface Residue Pairs of Protein Trimers. Lyu Y, Gong X. Molecules 25 E4353 (2020)


Reviews citing this publication (9)

  1. Processing ribonucleotides incorporated during eukaryotic DNA replication. Williams JS, Lujan SA, Kunkel TA. Nat. Rev. Mol. Cell Biol. 17 350-363 (2016)
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  9. The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders. Matz KM, Guzman RM, Goodman AG. Int Rev Cell Mol Biol 345 35-136 (2019)

Articles citing this publication (55)

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  7. RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. Pokatayev V, Hasin N, Chon H, Cerritelli SM, Sakhuja K, Ward JM, Morris HD, Yan N, Crouch RJ. J. Exp. Med. 213 329-336 (2016)
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  15. Rare coding variants and breast cancer risk: evaluation of susceptibility Loci identified in genome-wide association studies. Zhang Y, Long J, Lu W, Shu XO, Cai Q, Zheng Y, Li C, Li B, Gao YT, Zheng W. Cancer Epidemiol. Biomarkers Prev. 23 622-628 (2014)
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  20. A Conserved Interaction between a C-Terminal Motif in Norovirus VPg and the HEAT-1 Domain of eIF4G Is Essential for Translation Initiation. Leen EN, Sorgeloos F, Correia S, Chaudhry Y, Cannac F, Pastore C, Xu Y, Graham SC, Matthews SJ, Goodfellow IG, Curry S. PLoS Pathog. 12 e1005379 (2016)
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  22. Activity, stability, and structure of metagenome-derived LC11-RNase H1, a homolog of Sulfolobus tokodaii RNase H1. Nguyen TN, Angkawidjaja C, Kanaya E, Koga Y, Takano K, Kanaya S. Protein Sci. 21 553-561 (2012)
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  24. BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment. D'Alessandro G, Whelan DR, Howard SM, Vitelli V, Renaudin X, Adamowicz M, Iannelli F, Jones-Weinert CW, Lee M, Matti V, Lee WTC, Morten MJ, Venkitaraman AR, Cejka P, Rothenberg E, d'Adda di Fagagna F. Nat Commun 9 5376 (2018)
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  27. Structure and characterization of RNase H3 from Aquifex aeolicus. Jongruja N, You DJ, Angkawidjaja C, Kanaya E, Koga Y, Kanaya S. FEBS J. 279 2737-2753 (2012)
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  30. Unlike the Escherichia coli counterpart, archaeal RNase HII cannot process ribose monophosphate abasic sites and oxidized ribonucleotides embedded in DNA. Malfatti MC, Henneke G, Balachander S, Koh KD, Newnam G, Uehara R, Crouch RJ, Storici F, Tell G. J Biol Chem 294 13061-13072 (2019)
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  34. Signatures of TOP1 transcription-associated mutagenesis in cancer and germline. Reijns MAM, Parry DA, Williams TC, Nadeu F, Hindshaw RL, Rios Szwed DO, Nicholson MD, Carroll P, Boyle S, Royo R, Cornish AJ, Xiang H, Ridout K, Genomics England Research Consortium, Colorectal Cancer Domain UK 100,000 Genomes Project, Schuh A, Aden K, Palles C, Campo E, Stankovic T, Taylor MS, Jackson AP. Nature 602 623-631 (2022)
  35. A DOT1B/Ribonuclease H2 Protein Complex Is Involved in R-Loop Processing, Genomic Integrity, and Antigenic Variation in Trypanosoma brucei. Eisenhuth N, Vellmer T, Rauh ET, Butter F, Janzen CJ. mBio 12 e0135221 (2021)
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  38. Novel Escherichia coli active site dnaE alleles with altered base and sugar selectivity. Vaisman A, Łazowski K, Reijns MAM, Walsh E, McDonald JP, Moreno KC, Quiros DR, Schmidt M, Kranz H, Yang W, Makiela-Dzbenska K, Woodgate R. Mol Microbiol 116 909-925 (2021)
  39. Aicardi-Goutières Syndrome associated mutations of RNase H2B impair its interaction with ZMYM3 and the CoREST histone-modifying complex. Shapson-Coe A, Valeiras B, Wall C, Rada C. PLoS ONE 14 e0213553 (2019)
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  55. Val143 of human ribonuclease H2 is not critical for, but plays a role in determining catalytic activity and substrate specificity. Baba M, Kojima K, Nishimura T, Sugiura T, Takita T, Uehara R, Crouch RJ, Yasukawa K. PLoS One 15 e0228774 (2020)


Related citations provided by authors (1)

  1. The structure of the mammalian RNase H2 complex provides insight into RNA.NA hybrid processing to prevent immune dysfunction.. Shaban NM, Harvey S, Perrino FW, Hollis T J Biol Chem 285 3617-3624 (2010)

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