Control of structure-specific endonucleases to maintain genome stability
Key Points Structure-specific endonucleases (SSEs) process various types of DNA secondary structures that arise during DNA replication, repair, recombination and transcription, and are important for the maintenance of genome stability. Elaborate regulatory mechanisms ensure that SSEs act in an effic...
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| Vydané v: | Nature reviews. Molecular cell biology Ročník 18; číslo 5; s. 315 - 330 |
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| Hlavní autori: | , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
London
Nature Publishing Group UK
01.05.2017
Nature Publishing Group |
| Predmet: | |
| ISSN: | 1471-0072, 1471-0080, 1471-0080 |
| On-line prístup: | Získať plný text |
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| Shrnutí: | Key Points
Structure-specific endonucleases (SSEs) process various types of DNA secondary structures that arise during DNA replication, repair, recombination and transcription, and are important for the maintenance of genome stability.
Elaborate regulatory mechanisms ensure that SSEs act in an efficient, specific and timely manner so that they do not themselves become a source of genome instability.
The control of SSEs relies on a combination of catalytic regulation; modulation of their cellular localization, which regulates their targeting to the appropriate substrate or instead ensures their sequestration to reduce the risk of uncontrolled DNA processing; and protein turnover.
SSEs can function genome-wide, such as during the repair of DNA adducts by nucleotide excision repair, or their function can be specific to genomic loci that are prone to the formation of DNA secondary structures that need to be processed during replication and/or transcription. Such loci include, for example, the ribosomal DNA or telomeres, which contain DNA repeats, or regions that replicate late in S phase and therefore might not be replicated on time before the onset of mitosis, such as common fragile sites.
The control of SSEs is critical during DNA replication, during which inappropriate SSE activity, especially of MUS81 nucleases, can have dire consequences for genome stability.
Nuclease scaffolds are particularly important for the regulation of SSEs, by helping in their efficient recruitment to DNA and coordination with other factors. Nuclease scaffolds can directly modulate the catalytic activity of SSEs and change their substrate specificity. Some scaffolds are dedicated to the control of a single SSE, whereas others control several SSEs, either independently or by coordinating their activity within the same pathway.
Structure-specific endonucleases (SSEs) function in concert with other DNA-remodelling enzymes and cell cycle control machineries in processes such as DNA adduct repair, Holliday junction processing and the response to replication stress. As SSEs have specificity for DNA structures rather than sequence, tight regulation of their activity is important to ensure genome stability.
Structure-specific endonucleases (SSEs) have key roles in DNA replication, recombination and repair, and emerging roles in transcription. These enzymes have specificity for DNA secondary structure rather than for sequence, and therefore their activity must be precisely controlled to ensure genome stability. In this Review, we discuss how SSEs are controlled as part of genome maintenance pathways in eukaryotes, with an emphasis on the elaborate mechanisms that regulate the members of the major SSE families — including the xeroderma pigmentosum group F-complementing protein (XPF) and MMS and UV-sensitive protein 81 (MUS81)-dependent nucleases, and the flap endonuclease 1 (FEN1), XPG and XPG-like endonuclease 1 (GEN1) enzymes — during processes such as DNA adduct repair, Holliday junction processing and replication stress. We also discuss newly characterized connections between SSEs and other classes of DNA-remodelling enzymes and cell cycle control machineries, which reveal the importance of SSE scaffolds such as the synthetic lethal of unknown function 4 (SLX4) tumour suppressor for the maintenance of genome stability. |
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| Bibliografia: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 |
| ISSN: | 1471-0072 1471-0080 1471-0080 |
| DOI: | 10.1038/nrm.2016.177 |