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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.

Competing Interests: Declaration of interests The authors declare no competing interests.

Titel:	Active DNA damage eviction by HLTF stimulates nucleotide excision repair.
Autor/in / Beteiligte Person:	van Toorn M ; Turkyilmaz, Y ; Han, S ; Zhou, D ; Kim, HS ; Salas-Armenteros, I ; Kim, M ; Akita, M ; Wienholz, F ; Raams, A ; Ryu, E ; Kang, S ; Theil, AF ; Bezstarosti, K ; Tresini, M ; Giglia-Mari, G ; Demmers, JA ; Schärer, OD ; Choi, JH ; Vermeulen, W ; Marteijn, JA
Link:	Full Text Finder (Volltext)
Zeitschrift:	Molecular cell, Jg. 82 (2022-04-07), Heft 7, S. 1343-1358.e8
Veröffentlichung:	Cambridge Ma : Cell Press ; <i>Original Publication</i>: Cambridge, Mass. : Cell Press, c1997-, 2022
Medientyp:	academicJournal
ISSN:	1097-4164 (electronic)
DOI:	10.1016/j.molcel.2022.02.020
Schlagwort:	DNA genetics DNA metabolism DNA Damage DNA Replication DNA Repair DNA-Binding Proteins genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Mol Cell] 2022 Apr 07; Vol. 82 (7), pp. 1343-1358.e8. <i>Date of Electronic Publication: </i>2022 Mar 09. MeSH Terms: DNA Repair* ; DNA-Binding Proteins* / genetics ; DNA / genetics ; DNA / metabolism ; DNA Damage ; DNA Replication References: Nat Commun. 2019 Jun 28;10(1):2885. (PMID: 31253769) ; Nucleic Acids Res. 2018 Nov 30;46(21):11340-11356. (PMID: 30335157) ; Nucleic Acids Res. 2015 Dec 2;43(21):10277-91. (PMID: 26350214) ; Mol Cell Biol. 1997 Dec;17(12):7069-76. (PMID: 9372938) ; J Biol Chem. 2013 Jul 19;288(29):20918-20926. (PMID: 23749995) ; DNA Repair (Amst). 2004 Mar 4;3(3):277-87. (PMID: 15177043) ; PLoS Biol. 2009 Oct;7(10):e1000220. (PMID: 19841728) ; J Biol Chem. 2015 Nov 27;290(48):28812-21. (PMID: 26438822) ; Crit Rev Biochem Mol Biol. 2017 Dec;52(6):696-714. 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Active DNA damage eviction by HLTF stimulates nucleotide excision repair.