Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling

Ramhari Kumbhar (1) , Sophie Vidal-Eychenié (1) , Dimitrios-Georgios Kontopoulos (2) , Marion Larroque (3) , Christian Larroque (4) , J. Basbous (1) , Sofia Kossida (1, 5) , Cyril Ribeyre (1) , Angelos Constantinou (1)

1 IGH - Institut de génétique humaine
2 Department of Life Sciences
3 ICM - Institut régional de Cancérologie de Montpellier
4 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
5 IMGT - International ImMunoGeneTics Information System

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.

Domaines: Sciences du Vivant [q-bio]; Génétique

Ramhari Kumbhar, Sophie Vidal-Eychenié, Dimitrios-Georgios Kontopoulos, Marion Larroque, Christian Larroque, et al.. Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling. Life Science Alliance, 2018, 1 (3), pp.e201800096. ⟨10.26508/lsa.201800096⟩. ⟨hal-01980441⟩