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 cancer-suppression role.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- March 2008
- DOI:
- 10.1073/pnas.0800563105
- Bibcode:
- 2008PNAS..105.3768U
- Keywords:
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- yeast Rad5;
- damage bypass;
- K63 polyubiquitination;
- tumor suppressor;
- Biological Sciences:Biochemistry