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Mechanism of DNA-protein cross-link repair in S phase

Periodic Reporting for period 2 - DPC_REPAIR (Mechanism of DNA-protein cross-link repair in S phase)

Reporting period: 2018-07-01 to 2019-12-31

We are addressing how a specific type of DNA lesion known as DNA-protein crosslink is repaired during DNA replication.
This is highly relevant to society because DNA-protein crosslinks are highly cytotoxic lesions known to trigger cancer in humans. Moreover, DNA-protein crosslinks are the byproduct of most chemotherapeutic drugs used in the clinic to treat cancer.
Thus, if we can understand how DNA-protein crosslinks are repaired, we will be able to develop new treatments to fight cancer in the futur.
During the first 30 months of this project, we have studied how DNA protein crosslinks are repaired during DNA replication.

Particularly, we have delineated the molecular function of SPRTN in DPC repair and we provide the molecular events that activate and target the protease to DNA-protein crosslinks. Contrary to what was anticipated, SPRTN-mediated DPC degradation does not require DPC ubiquitylation. Instead the protease is activated when a nascent strand is extended to the lesion which appears to be the essential event that targets the protease.

These findings were recently published in Molecular Cell and were made open source:

https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30994-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276518309948%3Fshowall%3Dtrue
Our findings provide new and important mechanistic insights on how DNA-protein crosslinks are repaired which go well beyond the state of the art of the field. Moreover, they have identified new factors that participate in the repair reaction. These factors provide new attractive targets for drug development that could be used to sensitise cells to chemotherapeutic drugs.
Mechanisms of replication couple DPC proteolysis