Molecular mechanisms of DNA-protein crosslinks repair: Implications for cancer therapy.
Cells possess an elaborate genome maintenance apparatus, consisting of multiple DNA damage repair (DDR) and DNA damage tolerance pathways. Following DNA damage, sensor proteins recognise the DNA lesions and activate a complex signalling cascade, which marks the genomic region containing the DNA lesion, activate the optimal DNA repair pathway, and coordinates cell cycle progression and other DNA transactions during the repair process. DNA-protein cross-links (DPCs) are extremely bulky DNA lesions formed when proteins become covalently trapped on chromosomal DNA. Such events can occur spontaneously, as a result of cellular metabolism, or can be induced by exogenous sources. Because of their considerable size and their helix-distorting nature, DPCs interfere with different DNA processes, namely DNA replication, transcription, repair and segregation.
Although the existence of DPCs has been known for a long time, the mechanisms involved in the DPC-specific DDR are poorly understood. Recently, we discovered a specialised DNA repair pathway, the Replication-Coupled Proteolysis Repair (RC-PR). The DNA-dependent protease SPRTN cleaves DPCs during DNA replication, protecting replicative cells from DPC-induced genotoxicity. DPCs can also be removed by excision mechanisms, namely by Nucleotide Excision Repair and Homologous Recombination.
DPCs have been implicated in carcinogenesis by several studies. Mutations the SPRTN gene causes hepatocellular carcinoma both in humans and mice. SPRTN is mostly amplified in tumours with just only a few cases of deletions/mutation, suggesting the crucial importance of SPRTN and DPC repair for tumour survival and growth. Additionally, exposure to different DPC-inducing agents increases cancer risk both in mice and humans. Therefore, understand the mechanisms involved in the DPC-specific DDR, open a new avenue to identify additional targets of the DDR.
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford
Domain 1 - UMR 3347 / U1021 - Normal and pathological signaling