Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination

Ildiko Unk; Ildikó Hajdú; Károly Fátyol; Jerard Hurwitz; Jung Hoon Yoon; Louise Prakash; Satya Prakash; Lajos Haracska

doi:10.1073/pnas.0800563105

Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination

Ildiko Unk, Ildikó Hajdú, Károly Fátyol, Jerard Hurwitz, Jung Hoon Yoon, Louise Prakash, Satya Prakash, Lajos Haracska

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

191 Scopus citations

Abstract

Human helicase-like transcription factor (HLTF) is frequently inactivated in colorectal and gastric cancers. Here, we show that HLTF is a functional homologue of yeast Rad5 that promotes error-free replication through DNA lesions. HLTF and Rad5 share the same unique structural features, including a RING domain embedded within a SWI/SNF helicase domain and an HIRAN domain. We find that inactivation of HLTF renders human cells sensitive to UV and other DNA-damaging agents and that HLTF complements the UV sensitivity of a rad5Δ yeast strain. Also, similar to Rad5, HLTF physically interacts with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes and promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen at its Lys-164 residue. A requirement of HLTF for error-free postreplication repair of damaged DNA is in keeping with its cancersuppression role.

Original language	English (US)
Pages (from-to)	3768-3773
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	105
Issue number	10
DOIs	https://doi.org/10.1073/pnas.0800563105
State	Published - Mar 25 2008

Keywords

Damage bypass
K63 polyubiquitination
Tumor suppressor
Yeast Rad5

ASJC Scopus subject areas

General

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10.1073/pnas.0800563105

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title = "Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination",

abstract = "Human helicase-like transcription factor (HLTF) is frequently inactivated in colorectal and gastric cancers. Here, we show that HLTF is a functional homologue of yeast Rad5 that promotes error-free replication through DNA lesions. HLTF and Rad5 share the same unique structural features, including a RING domain embedded within a SWI/SNF helicase domain and an HIRAN domain. We find that inactivation of HLTF renders human cells sensitive to UV and other DNA-damaging agents and that HLTF complements the UV sensitivity of a rad5Δ yeast strain. Also, similar to Rad5, HLTF physically interacts with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes and promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen at its Lys-164 residue. A requirement of HLTF for error-free postreplication repair of damaged DNA is in keeping with its cancersuppression role.",

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T1 - Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination

AU - Unk, Ildiko

AU - Hajdú, Ildikó

AU - Fátyol, Károly

AU - Hurwitz, Jerard

AU - Yoon, Jung Hoon

AU - Prakash, Louise

AU - Prakash, Satya

AU - Haracska, Lajos

PY - 2008/3/25

Y1 - 2008/3/25

N2 - Human helicase-like transcription factor (HLTF) is frequently inactivated in colorectal and gastric cancers. Here, we show that HLTF is a functional homologue of yeast Rad5 that promotes error-free replication through DNA lesions. HLTF and Rad5 share the same unique structural features, including a RING domain embedded within a SWI/SNF helicase domain and an HIRAN domain. We find that inactivation of HLTF renders human cells sensitive to UV and other DNA-damaging agents and that HLTF complements the UV sensitivity of a rad5Δ yeast strain. Also, similar to Rad5, HLTF physically interacts with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes and promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen at its Lys-164 residue. A requirement of HLTF for error-free postreplication repair of damaged DNA is in keeping with its cancersuppression role.

AB - Human helicase-like transcription factor (HLTF) is frequently inactivated in colorectal and gastric cancers. Here, we show that HLTF is a functional homologue of yeast Rad5 that promotes error-free replication through DNA lesions. HLTF and Rad5 share the same unique structural features, including a RING domain embedded within a SWI/SNF helicase domain and an HIRAN domain. We find that inactivation of HLTF renders human cells sensitive to UV and other DNA-damaging agents and that HLTF complements the UV sensitivity of a rad5Δ yeast strain. Also, similar to Rad5, HLTF physically interacts with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes and promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen at its Lys-164 residue. A requirement of HLTF for error-free postreplication repair of damaged DNA is in keeping with its cancersuppression role.

KW - Damage bypass

KW - K63 polyubiquitination

KW - Tumor suppressor

KW - Yeast Rad5

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Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination

Abstract

Keywords

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