6kcs | pdb_00006kcs

Crystal structure of HIRAN domain of HLTF in complex with duplex DNA

Structural highlights

6kcs is a 2 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 2.1Å
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

Replication fork regression is a mechanism to rescue a stalled fork by various replication stresses, such as DNA lesions. Helicase-like transcription factor, a SNF2 translocase, plays a central role in the fork regression and its N-terminal domain, HIRAN (HIP116 and Rad5 N-terminal), binds the 3'-hydroxy group of single-stranded DNA. Furthermore, HIRAN is supposed to bind double-stranded DNA (dsDNA) and involved in strand separation in the fork regression, whereas structural basis for mechanisms underlying dsDNA binding and strand separation by HIRAN are still unclear. Here, we report the crystal structure of HIRAN bound to duplex DNA. The structure reveals that HIRAN binds the 3'-hydroxy group of DNA and unexpectedly unwinds three nucleobases of the duplex. Phe-142 is involved in the dsDNA binding and the strand separation. In addition, the structure unravels the mechanism underlying sequence-independent recognition for purine bases by HIRAN, where the N-glycosidic bond adopts syn conformation. Our findings indicate direct involvement of HIRAN in the fork regression by separating of the daughter strand from the parental template.

Structure of HIRAN domain of human HLTF bound to duplex DNA provides structural basis for DNA unwinding to initiate replication fork regression.,Hishiki A, Sato M, Hashimoto H J Biochem. 2020 Jun 1;167(6):597-602. doi: 10.1093/jb/mvaa008. PMID:31960921^[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
↑ Hishiki A, Sato M, Hashimoto H. Structure of HIRAN domain of human HLTF bound to duplex DNA provides structural basis for DNA unwinding to initiate replication fork regression. J Biochem. 2020 Jun 1;167(6):597-602. doi: 10.1093/jb/mvaa008. PMID:31960921 doi:https://dx.doi.org/10.1093/jb/mvaa008

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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] Hishiki A, Sato M, Hashimoto H. Structure of HIRAN domain of human HLTF bound to duplex DNA provides structural basis for DNA unwinding to initiate replication fork regression. J Biochem. 2020 Jun 1;167(6):597-602. doi: 10.1093/jb/mvaa008. PMID:31960921 doi:https://dx.doi.org/10.1093/jb/mvaa008

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6kcs | pdb_00006kcs

Crystal structure of HIRAN domain of HLTF in complex with duplex DNA

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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