Proteomics

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CRISPR screening identifies C1orf112 as a novel modulator of the response to ICLs


ABSTRACT: DNA interstrand crosslinks (ICLs) are highly cytotoxic DNA lesions that are commonly induced by endogenous metabolic processes and chemotherapeutic drugs, such as cisplatin. To prevent detrimental effects associated with ICLs, such as interference with both transcription and replication, cells rely on a complex coordination of different DNA repair pathways, including Fanconi Anemia (FA) and homologous recombination (HR), for their resolution. To unveil the breadth of factors that plays a role in this response, we performed CRISPR-based genome-wide screens treated with the clinically relevant cyclophosphamide agent. This approach, along with a fluorescence-based competition assay, defined C1orf112 as a novel modulator of the response to ICLs-inducing agents. Subsequent analysis showed that depletion of C1orf112 impairs genomic stability by increasing spontaneous levels of gamma-H2AX, micronuclei, and 53BP1-nuclear bodies. Using immunofluorescence approaches, we found that C1orf112 acts downstream of the FA pathways and is required for resolving ICL-induced RAD51 foci. Consistently, our results show that C1orf112 is required for homology-directed DNA repair, including HR and single-strand annealing. Proximal mapping of C1orf112 using TurboID technology identified the AAA+ ATPase FIGNL1 as a constitutive interactor and functional characterization of this complex shows that these C1orf112 and FIGNL1 cooperate in the unloading of RAD51 at ICL-induced lesion. Altogether, our findings reveal C1orf112 as a previously unidentified regulator of the AAA+ ATPase FIGNL1 in the resolution of ICLs by homology-directed DNA repair pathways.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Alexandre Orthwein  

PROVIDER: MSV000089544 | MassIVE | Wed May 25 08:38:00 BST 2022

REPOSITORIES: MassIVE

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