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

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

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23 Citations (Scopus)


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. In more general terms, 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.

Original languageEnglish
Pages (from-to)10277-10291
Number of pages15
JournalNucleic Acids Research
Issue number21
Publication statusPublished - 2015


ASJC Scopus subject areas

  • Genetics

Cite this

Achar, Y. J., Balogh, D., Neculai, D., Juhasz, S., Morocz, M., Gali, H., Dhe-Paganon, S., Venclovas, Č., & Haracska, L. (2015). Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling. Nucleic Acids Research, 43(21), 10277-10291.