Covalent DNA-protein cross-links (DPCs) impede replication fork progression and threaten genomic integrity. In two studies published in Cell and Molecular Cell Markus Räschle and colleagues identify factors which facilitate bypass and repair of these roadblocks. Using quantitative mass spectrometry, they identify an auxillary helicase, RTEL1, that helps the replisome to translocate passed the DNA lesions. Intriguingly, bypass of an intact protein DNA crosslink could directly be observed in single molecule experiments.
To identify the factors required for removal of such DNA lesions, the scientists comprehensively monitored protein recruitment to damaged plasmids undergoing replication and repair. From the temporal profiles two proteases, SPRTN and the Proteasome, were identified to degrade the crosslinked protein from the DNA. Further mechanistic studies revealed how the protealytic activity of SPRTN and the Proteasome is controlled and activated only in the context of ongoing DNA replication.
The CMG Helicase Bypasses DNA-Protein Cross-Links To Facilitate Their Repair
Sparks JL, Chistol G, Gao A.O, Räschle M, Larsen NB, Mann M, Duxin JP, Walter JC.
https://doi.org/10.1016/j.cell.2018.10.053
Replication-Coupled DNA-Protein Crosslink Repair by SPRTN and the Proteasome in Xenopus Egg Extracts
Larsen NB, Gao, AO, Sparks JL, Gallina I, Wu AR, Mann M, Räschle M, Walter JC, Duxin J.
https://doi.org/10.1016/j.molcel.2018.11.024