From incision to excision: active DNA damage eviction by HLTF stimulates repair

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 shows a dual incision-dependent recruitment of HLTF to the NER incision complex, mediated by HLTF’s HIRAN domain that binds 3’-OH single-stranded DNA ends. HLTF’s translocase motor subsequently promotes dissociation of incised oligonucleotides together with members of the stably damage-bound incision complex to allow efficient PCNA loading and initiation of repair synthesis. Our findings uncover HLTF as an important NER factor that actively evicts DNA damage, thereby providing an additional quality control by coordinating the transition between the excision and DNA synthesis steps to safeguard genome integrity.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fibroblast

DISEASE(S): Cockayne Syndrome

SUBMITTER: Jeroen Demmers  

LAB HEAD: Jeroen Demmers

PROVIDER: PXD031243 | Pride | 2023-05-10

REPOSITORIES: Pride