The Nup84 complex coordinates the DNA damage response to warrant genome integrity

Abstract

DNA lesions interfere with cellular processes such as transcription and replication and need to be adequately resolved to warrant genome integrity. Beyond their primary role in molecule transport, nuclear pore complexes (NPCs) function in other processes such as transcription, nuclear organization and DNA double strand break (DSB) repair. Here we found that the removal of UV-induced DNA lesions by nucleotide excision repair (NER) is compromised in the absence of the Nup84 nuclear pore component. Importantly, nup84Δ cells show an exacerbated sensitivity to UV in early S phase and delayed replication fork progression, suggesting that unrepaired spontaneous DNA lesions persist during S phase. In addition, nup84Δ cells are defective in the repair of replication-born DSBs by sister chromatid recombination (SCR) and rely on post-replicative repair functions for normal proliferation, indicating dysfunctions in the cellular pathways that enable replication on damaged DNA templates. Altogether, our data reveal a central role of the NPC in the DNA damage response to facilitate replication progression through damaged DNA templates by promoting efficient NER and SCR and preventing chromosomal rearrangements. ; European Research Council [ERC2014 AdG669898 TARLOOP to A.A.]; Spanish Ministry of Economy and Competitiveness [BFU2016-75058-P to A.A.]; Junta de Andalucía [PA12-BIO1238 to A.A.]; European Union Regional Funds (FEDER). Funding for open access charge: European Research Council [ERC2014 AdG669898 TARLOOP]; Spanish Ministry of Economy and Competitiveness [BFU2016-75058-P].