title: Solution NMR structure of the HLTF HIRAN domain: a conserved module in SWI2/SNF2 DNA damage tolerance proteins.
abstract: HLTF is a SWI2/SNF2-family ATP-dependent chromatin remodeling enzyme that acts in the error-free branch of DNA damage tolerance (DDT), a cellular mechanism that enables replication of damaged DNA while leaving damage repair for a later time. Human HLTF and a closely related protein SHPRH, as well as their yeast homologue Rad5, are multi-functional enzymes that share E3 ubiquitin-ligase activity required for activation of the error-free DDT. HLTF and Rad5 also function as ATP-dependent dsDNA translocases and possess replication fork reversal activities. Thus, they can convert Y-shaped replication forks into X-shaped Holliday junction structures that allow error-free replication over DNA lesions. The fork reversal activity of HLTF is dependent on 3'-ssDNA-end binding activity of its N-terminal HIRAN domain. Here we present the solution NMR structure of the human HLTF HIRAN domain, an OB-like fold module found in organisms from bacteria (as a stand-alone domain) to plants, fungi and metazoan (in combination with SWI2/SNF2 helicase-like domain). The obtained structure of free HLTF HIRAN is similar to recently reported structures of its DNA bound form, while the NMR analysis also reveals that the DNA binding site of the free domain exhibits conformational heterogeneity. Sequence comparison of N-terminal regions of HLTF, SHPRH and Rad5 aided by knowledge of the HLTF HIRAN structure suggests that the SHPRH N-terminus also includes an uncharacterized structured module, exhibiting weak sequence similarity with HIRAN regions of HLTF and Rad5, and potentially playing a similar functional role.
authors: Department of Molecular Biology and Biophysics, University of Connecticut Health, Farmington, CT, 06030, USA.
authors: Dmitry M
authors: DM
authors: Korzhnev
authors: School of Medicine, Zhejiang University, Hangzhou, China.
authors: Dante
authors: D
authors: Neculai
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors: Sirano
authors: S
authors: Dhe-Paganon
authors: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.|Department of Medical Biophysics, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors: Cheryl H
authors: CH
authors: Arrowsmith
authors: Department of Molecular Biology and Biophysics, University of Connecticut Health, Farmington, CT, 06030, USA. bezsonova@uchc.edu.
authors: Irina
authors: I
authors: Bezsonova
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D012996:Solutions; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C100023:HLTF protein, human; D012996:Solutions; D014157:Transcription Factors
keywords: DNA damage tolerance; DNA replication; HLTF; Helicase-like transcription factor