Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling

Achar, Yathish Jagadheesh; Balogh, David; Neculai, Dante; Juhasz, Szilvia; Morocz, Monika; Gali, Himabindu; Dhe-Paganon, Sirano; Venclovas, Česlovas; Haracska, Lajos

doi:10.1093/nar/gkv896

Title: Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling

Journal Article · Tue Sep 08 00:00:00 EDT 2015 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkv896· OSTI ID:1223716

Achar, Yathish Jagadheesh ^[1]; Balogh, David ^[1]; Neculai, Dante ^[2]; Juhasz, Szilvia ^[1]; Morocz, Monika ^[1]; Gali, Himabindu ^[1]; Dhe-Paganon, Sirano ^[3]; Venclovas, Česlovas ^[4]; Haracska, Lajos ^[1]

Hungarian Academy of Sciences, Szeged (Hungary)
Zhejiang Univ., Hangzhou (China)
Dana Farber Cancer Institute, Boston, MA (United States)
Vilnius Univ., Vilnius (Lithuania)

Defects in the ability to respond properly to an unrepaired DNA lesion blocking replication promote genomic instability and cancer. Human HLTF, implicated in error-free replication of damaged DNA and tumour suppression, exhibits a HIRAN domain, a RING domain, and a SWI/SNF domain facilitating DNA-binding, PCNA-polyubiquitin-ligase, and dsDNA-translocase activities, respectively. Here, we investigate the mechanism of HLTF action with emphasis on its HIRAN domain. We found that in cells HLTF promotes the filling-in of gaps left opposite damaged DNA during replication, and this postreplication repair function depends on its HIRAN domain. Our biochemical assays show that HIRAN domain mutant HLTF proteins retain their ubiquitin ligase, ATPase and dsDNA translocase activities but are impaired in binding to a model replication fork. These data and our structural study indicate that the HIRAN domain recruits HLTF to a stalled replication fork, and it also provides the direction for the movement of the dsDNA translocase motor domain for fork reversal. We suggest functional similarities between the HIRAN, the OB, the HARP2, and other domains found in certain motor proteins, which may explain why only a subset of DNA translocases can carry out fork reversal.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1223716

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 47 works

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Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA Leung, Wendy; Baxley, Ryan; Moldovan, George-Lucian Genes, Vol. 10, Issue 1 https://doi.org/10.3390/genes10010010	journal	December 2018
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