期刊
MOLECULAR CELL
卷 64, 期 4, 页码 688-703出版社
CELL PRESS
DOI: 10.1016/j.molcel.2016.09.031
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资金
- Cancer Prevention and Research Institute of Texas
- Robert A. Welch Chemistry Chair
- European Molecular Biology Organization (EMBO) [ALTF 470-2015]
- EMBO [ALTF 1656-2014]
- Francis Crick Institute - Cancer Research UK [FC0010048]
- UK Medical Research Council [FC0010048]
- Wellcome Trust [FC0010048]
- European Research Council (ERC)
- Wellcome Trust
- Wellcome Trust [104558/Z/14/Z] Funding Source: Wellcome Trust
- MRC [MC_U105178788] Funding Source: UKRI
- Cancer Research UK [11581] Funding Source: researchfish
- Medical Research Council [MC_U105178788] Funding Source: researchfish
- The Francis Crick Institute [10267] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10048] Funding Source: researchfish
- Wellcome Trust [104558/Z/14/Z] Funding Source: researchfish
Covalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription. Little was known about DPC-specific repair mechanisms until the recent identification of a DPC-processing protease in yeast. The existence of a DPC protease in higher eukaryotes is inferred from data in Xenopus laevis egg extracts, but its identity remains elusive. Here we identify the metalloprotease SPRTN as the DPC protease acting in metazoans. Loss of SPRTN results in failure to repair DPCs and hypersensitivity to DPC-inducing agents. SPRTN accomplishes DPC processing through a unique DNA-induced protease activity, which is controlled by several sophisticated regulatory mechanisms. Cellular, biochemical, and structural studies define a DNA switch triggering its protease activity, a ubiquitin switch controlling SPRTN chromatin accessibility, and regulatory autocatalytic cleavage. Our data also provide a molecular explanation on how SPRTN deficiency causes the premature aging and cancer predisposition disorder Ruijs-Aalfs syndrome.
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