Abstract
The DNA damage response (DDR) ensures cellular adaptation to genotoxic insults. In the crowded environment of the nucleus, the assembly of productive DDR complexes requires multiple protein modifications. How the apical E1 ubiquitin activation enzyme UBA1 integrates spatially and temporally in the DDR remains elusive. Using a human cell-free system, we show that poly(ADP-ribose) polymerase 1 promotes the recruitment of UBA1 to DNA. We find that the association of UBA1 with poly(ADP-ribosyl)ated protein-DNA complexes is necessary for the phosphorylation replication protein A and checkpoint kinase 1 by the serine/threonine protein kinase ataxia-telangiectasia and RAD3-related, a prototypal response to DNA damage. UBA1 interacts directly with poly(ADP-ribose) via a solvent-accessible and positively charged patch conserved in the Animalia kingdom but not in Fungi. Thus, ubiquitin activation can anchor to poly(ADP-ribose)-seeded protein assemblies, ensuring the formation of functional ataxia-telangiectasia mutated and RAD3-related-signalling complexes.
Highlights
The DNA damage response (DDR) is a signal transduction pathway that detects lesions in DNA and ensures cell and organismal survival through coordination of DNA repair and DNA replication with physiological processes, including cell cycle progression and transcription (Matsuoka et al, 2007; Ciccia & Elledge, 2010)
Among the most prominent DNA-bound proteins, we identified DNA-PKcs, PARP1, UBA1, as well as RNA-processing proteins such as fused in liposarcoma (FUS) and HNRNPUL1 (Fig 1B)
Extensive posttranslational modifications of chromatin-associated proteins are required for DNA damage signalling and for the coordinated recruitment of DNA repair proteins at DNA damage sites (Ciccia & Elledge, 2010; Dantuma & van Attikum, 2016; Schwertman et al, 2016)
Summary
The DNA damage response (DDR) is a signal transduction pathway that detects lesions in DNA and ensures cell and organismal survival through coordination of DNA repair and DNA replication with physiological processes, including cell cycle progression and transcription (Matsuoka et al, 2007; Ciccia & Elledge, 2010). At the apex of the DDR, the master checkpoint kinases ataxia telangiectasia mutated (ATM) and ataxia-telangiectasia and RAD3-related (ATR) and the poly(ADP-ribose) (pADPr) polymerases (PARP1) sense and signal double-strand DNA (dsDNA) breaks (DSBs) and the slowing or stalling of replication forks (Ciccia & Elledge, 2010; Blackford & Jackson, 2017; Ray Chaudhuri and Nussenzweig, 2017; Saldivar et al, 2017). One of the earliest responses to DNA damage is the conjugation by PARP1 of pADPr to substrate proteins, including itself, at DNA breaks and stalled replication forks (Caldecott et al, 1996; Bryant et al, 2009; Langelier et al, 2011). Phosphorylation of FUS at multiple consensus serine/threonine glutamine sites by DNA-PKcs counteracts the self-association and aggregation of its lowcomplexity domain (Monahan et al, 2017)
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