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  • Active DNA damage eviction by HLTF stimulates nucleotide excision repair.

Active DNA damage eviction by HLTF stimulates nucleotide excision repair.

Molecular cell (2022-03-11)
Marvin van Toorn, Yasemin Turkyilmaz, Sueji Han, Di Zhou, Hyun-Suk Kim, Irene Salas-Armenteros, Mihyun Kim, Masaki Akita, Franziska Wienholz, Anja Raams, Eunjin Ryu, Sukhyun Kang, Arjan F Theil, Karel Bezstarosti, Maria Tresini, Giuseppina Giglia-Mari, Jeroen A Demmers, Orlando D Schärer, Jun-Hyuk Choi, Wim Vermeulen, Jurgen A Marteijn
ABSTRACT

Nucleotide excision repair (NER) counteracts the onset of cancer and aging by removing helix-distorting DNA lesions via a "cut-and-patch"-type reaction. The regulatory mechanisms that drive NER through its successive damage recognition, verification, incision, and gap restoration reaction steps remain elusive. Here, we show that the RAD5-related translocase HLTF facilitates repair through active eviction of incised damaged DNA together with associated repair proteins. Our data show a dual-incision-dependent recruitment of HLTF to the NER incision complex, which is mediated by HLTF's HIRAN domain that binds 3'-OH single-stranded DNA ends. HLTF's translocase motor subsequently promotes the dissociation of the stably damage-bound incision complex together with the incised oligonucleotide, allowing for an efficient PCNA loading and initiation of repair synthesis. Our findings uncover HLTF as an important NER factor that actively evicts DNA damage, thereby providing additional quality control by coordinating the transition between the excision and DNA synthesis steps to safeguard genome integrity.

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