4s0n

Crystal Structure of HLTF HIRAN Domain bound to DNA

Structural highlights

4s0n is a 8 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.501Å
Ligands:	GOL, NA, TMP
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HLTF_HUMAN Has both helicase and E3 ubiquitin ligase activities. Possesses intrinsic ATP-dependent nucleosome-remodeling activity; This activity may be required for transcriptional activation or repression of specific target promoters (By similarity). These may include the SERPINE1 and HIV-1 promoters and the SV40 enhancer, to which this protein can bind directly. Plays a role in error-free postreplication repair (PRR) of damaged DNA and maintains genomic stability through acting as a ubiquitin ligase for 'Lys-63'-linked polyubiquitination of chromatin-bound PCNA.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Stalled replication forks are a critical problem for the cell because they can lead to complex genome rearrangements that underlie cell death and disease. Processes such as DNA damage tolerance and replication fork reversal protect stalled forks from these events. A central mediator of these DNA damage responses in humans is the Rad5-related DNA translocase, HLTF. Here, we present biochemical and structural evidence that the HIRAN domain, an ancient and conserved domain found in HLTF and other DNA processing proteins, is a modified oligonucleotide/oligosaccharide (OB) fold that binds to 3' ssDNA ends. We demonstrate that the HIRAN domain promotes HLTF-dependent fork reversal in vitro through its interaction with 3' ssDNA ends found at forks. Finally, we show that HLTF restrains replication fork progression in cells in a HIRAN-dependent manner. These findings establish a mechanism of HLTF-mediated fork reversal and provide insight into the requirement for distinct fork remodeling activities in the cell.

HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal.,Kile AC, Chavez DA, Bacal J, Eldirany S, Korzhnev DM, Bezsonova I, Eichman BF, Cimprich KA Mol Cell. 2015 Jun 18;58(6):1090-100. doi: 10.1016/j.molcel.2015.05.013. Epub, 2015 Jun 4. PMID:26051180^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ding H, Benotmane AM, Suske G, Collen D, Belayew A. Functional interactions between Sp1 or Sp3 and the helicase-like transcription factor mediate basal expression from the human plasminogen activator inhibitor-1 gene. J Biol Chem. 1999 Jul 9;274(28):19573-80. PMID:10391891
↑ Unk I, Hajdu I, Fatyol K, Hurwitz J, Yoon JH, Prakash L, Prakash S, Haracska L. Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3768-73. doi:, 10.1073/pnas.0800563105. Epub 2008 Mar 3. PMID:18316726 doi:https://dx.doi.org/10.1073/pnas.0800563105
↑ Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K. Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12411-6. Epub 2008 Aug 21. PMID:18719106 doi:0805685105
↑ Sheridan PL, Schorpp M, Voz ML, Jones KA. Cloning of an SNF2/SWI2-related protein that binds specifically to the SPH motifs of the SV40 enhancer and to the HIV-1 promoter. J Biol Chem. 1995 Mar 3;270(9):4575-87. PMID:7876228
↑ Ding H, Descheemaeker K, Marynen P, Nelles L, Carvalho T, Carmo-Fonseca M, Collen D, Belayew A. Characterization of a helicase-like transcription factor involved in the expression of the human plasminogen activator inhibitor-1 gene. DNA Cell Biol. 1996 Jun;15(6):429-42. PMID:8672239
↑ Gong X, Kaushal S, Ceccarelli E, Bogdanova N, Neville C, Nguyen T, Clark H, Khatib ZA, Valentine M, Look AT, Rosenthal N. Developmental regulation of Zbu1, a DNA-binding member of the SWI2/SNF2 family. Dev Biol. 1997 Mar 15;183(2):166-82. PMID:9126292 doi:https://dx.doi.org/10.1006/dbio.1996.8486
↑ Kile AC, Chavez DA, Bacal J, Eldirany S, Korzhnev DM, Bezsonova I, Eichman BF, Cimprich KA. HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal. Mol Cell. 2015 Jun 18;58(6):1090-100. doi: 10.1016/j.molcel.2015.05.013. Epub, 2015 Jun 4. PMID:26051180 doi:https://dx.doi.org/10.1016/j.molcel.2015.05.013

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OCA

[1] Ding H, Benotmane AM, Suske G, Collen D, Belayew A. Functional interactions between Sp1 or Sp3 and the helicase-like transcription factor mediate basal expression from the human plasminogen activator inhibitor-1 gene. J Biol Chem. 1999 Jul 9;274(28):19573-80. PMID:10391891

[2] Unk I, Hajdu I, Fatyol K, Hurwitz J, Yoon JH, Prakash L, Prakash S, Haracska L. Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3768-73. doi:, 10.1073/pnas.0800563105. Epub 2008 Mar 3. PMID:18316726 doi:https://dx.doi.org/10.1073/pnas.0800563105

[3] Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K. Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12411-6. Epub 2008 Aug 21. PMID:18719106 doi:0805685105

[4] Sheridan PL, Schorpp M, Voz ML, Jones KA. Cloning of an SNF2/SWI2-related protein that binds specifically to the SPH motifs of the SV40 enhancer and to the HIV-1 promoter. J Biol Chem. 1995 Mar 3;270(9):4575-87. PMID:7876228

[5] Ding H, Descheemaeker K, Marynen P, Nelles L, Carvalho T, Carmo-Fonseca M, Collen D, Belayew A. Characterization of a helicase-like transcription factor involved in the expression of the human plasminogen activator inhibitor-1 gene. DNA Cell Biol. 1996 Jun;15(6):429-42. PMID:8672239

[6] Gong X, Kaushal S, Ceccarelli E, Bogdanova N, Neville C, Nguyen T, Clark H, Khatib ZA, Valentine M, Look AT, Rosenthal N. Developmental regulation of Zbu1, a DNA-binding member of the SWI2/SNF2 family. Dev Biol. 1997 Mar 15;183(2):166-82. PMID:9126292 doi:https://dx.doi.org/10.1006/dbio.1996.8486

[7] Kile AC, Chavez DA, Bacal J, Eldirany S, Korzhnev DM, Bezsonova I, Eichman BF, Cimprich KA. HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal. Mol Cell. 2015 Jun 18;58(6):1090-100. doi: 10.1016/j.molcel.2015.05.013. Epub, 2015 Jun 4. PMID:26051180 doi:https://dx.doi.org/10.1016/j.molcel.2015.05.013

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4s0n

Crystal Structure of HLTF HIRAN Domain bound to DNA

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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