期刊
DNA REPAIR
卷 25, 期 -, 页码 84-96出版社
ELSEVIER
DOI: 10.1016/j.dnarep.2014.10.011
关键词
Common fragile sites; DNA replication stress; POLD3; Mass spectrometry; SUMOylation
资金
- Nordea Foundation
- Danish Medical Research Council
- Danish Natural Sciences Research Council
- Faculty of Health and Medical Sciences, University of Copenhagen
- Emmy Noether Program of the German Research Foundation (DFG) [BE 5342/1-1]
- Novo Nordisk Foundation Center for Protein Research [PI Chunaram Choudhary, PI Niels Mailand] Funding Source: researchfish
SUMOylation is a form of post-translational modification involving covalent attachment of SUMO (Small Ubiquitin-like Modifier) polypeptides to specific lysine residues in the target protein. In human cells, there are four SUMO proteins, SUMO1-4, with SUMO2 and SUMO3 forming a closely related subfamily. SUMO2/3, in contrast to SUMO1, are predominantly involved in the cellular response to certain stresses, including heat shock. Substantial evidence from studies in yeast has shown that SUMOylation plays an important role in the regulation of DNA replication and repair. Here, we report a proteomic analysis of proteins modified by SUMO2 in response to DNA replication stress in S phase in human cells. We have identified a panel of 22 SUMO2 targets with increased SUMOylation during DNA replication stress, many of which play key functions within the DNA replication machinery and/or in the cellular response to DNA damage. Interestingly, POLD3 was found modified most significantly in response to a low dose aphidicolin treatment protocol that promotes common fragile site (CFS) breakage. POLD3 is the human ortholog of POL32 in budding yeast, and has been shown to act during break-induced recombinational repair. We have also shown that deficiency of POLD3 leads to an increase in RPA-bound ssDNA when cells are under replication stress, suggesting that POLD3 plays a role in the cellular response to DNA replication stress. Considering that DNA replication stress is a source of genome instability, and that excessive replication stress is a hallmark of pre-neoplastic and tumor cells, our characterization of SUMO2 targets during a perturbed S-phase should provide a valuable resource for future functional studies in the fields of DNA metabolism and cancer biology. (C) 2014 Elsevier B.V. All rights reserved.
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