Regulation of Structure-Specific Endonucleases in Replication Stress

Kim, Seong M.; Forsburg, Susan L.

doi:10.3390/genes9120634

Cited by 12 publications

(11 citation statements)

References 160 publications

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“…Excision of eccDNA requires two additional strand cleavages beyond the initiating DSB, and this is not a favoured outcome of intrachromosomal strand invasion ( Figure 6). Helicases such as Sgs1 will dissolve D-loops formed by strand invasion to minimise rearrangements during DSB repair [70], and the activity of structure specific endonuclease enzymes capable of cleaving the nicked Holliday Junctions in a D-loop is tightly restricted to G2/M (reviewed in [71]). Nonetheless, an endonuclease activity is required and we find Mus81, which has a strong preference for cleaving nicked Holliday Junction intermediates, to be critical for eccDNA formation.…”

Section: Discussionmentioning

confidence: 99%

Transcription-induced formation of extrachromosomal DNA during yeast ageing

Hull

King

Pizza

et al. 2019

Preprint

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Extrachromosomal circular DNA (eccDNA) facilitates adaptive evolution by allowing rapid and extensive gene copy number variation, and is implicated in the pathology of cancer and ageing. Here, we demonstrate that yeast aged under environmental copper accumulate high levels of eccDNA containing the copper resistance gene CUP1. Transcription of CUP1 causes CUP1 eccDNA accumulation, which occurs in the absence of phenotypic selection. We have developed a sensitive and quantitative eccDNA sequencing pipeline that reveals CUP1 eccDNA accumulation on copper exposure to be exquisitely site specific, with no other detectable changes across the eccDNA complement. eccDNA forms de novo from the CUP1 locus through processing of DNA double-strand breaks (DSBs) by Sae2 / Mre11 and Mus81, and genome-wide analyses show that other protein coding eccDNA species in aged yeast share a similar biogenesis pathway. Although abundant we find that CUP1 eccDNA does not replicate efficiently, and high copy numbers in aged cells arise through frequent formation events combined with asymmetric DNA segregation. The transcriptional stimulation of CUP1 eccDNA formation shows that age-linked genetic change varies with transcription pattern, resulting in gene copy number profiles tailored by environment.

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Section: Discussionmentioning

confidence: 99%

Transcription-induced formation of extrachromosomal DNA during yeast ageing

Hull

King

Pizza

et al. 2019

Preprint

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“…To maintain genome stability and prevent unwanted DNA breaks, the activities of SSEs must be tightly coordinated with cell cycle and DNA damage response [3,4]. Previous studies showed that cell cycle kinases [72][73][74][75][76][77] and checkpoint kinases [17,74,78,79] play key roles in the regulation of SSEs.…”

Section: Discussionmentioning

confidence: 99%

“…Structure-specific endonucleases (SSEs) play crucial roles in the maintenance of genome stability by processing DNA intermediates during DNA replication, recombination, and repair [1,2]. Tight control of these nucleases is critical for accurately processing specific DNA structures without causing unnecessary DNA lesions [3,4]; however, the molecular mechanisms underlying the regulation of these nucleases have not been sufficiently revealed.…”

Section: Introductionmentioning

confidence: 99%

CRL4Cdt2 ubiquitin ligase regulates Dna2 and Rad16 (XPF) nucleases by targeting Pxd1 for degradation

et al. 2020

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Structure-specific endonucleases (SSEs) play key roles in DNA replication, recombination, and repair. SSEs must be tightly regulated to ensure genome stability but their regulatory mechanisms remain incompletely understood. Here, we show that in the fission yeast Schizosaccharomyces pombe, the activities of two SSEs, Dna2 and Rad16 (ortholog of human XPF), are temporally controlled during the cell cycle by the CRL4 Cdt2 ubiquitin ligase. CRL4 Cdt2 targets Pxd1, an inhibitor of Dna2 and an activator of Rad16, for degradation in S phase. The ubiquitination and degradation of Pxd1 is dependent on CRL4 Cdt2 , PCNA, and a PCNA-binding degron motif on Pxd1. CRL4 Cdt2-mediated Pxd1 degradation prevents Pxd1 from interfering with the normal S-phase functions of Dna2. Moreover, Pxd1 degradation leads to a reduction of Rad16 nuclease activity in S phase, and restrains Rad16-mediated single-strand annealing, a hazardous pathway of repairing double-strand breaks. These results demonstrate a new role of the CRL4 Cdt2 ubiquitin ligase in genome stability maintenance and shed new light on how SSE activities are regulated during the cell cycle.

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“…In contrast to the classic resolvase RuvC from bacteria [69], the eukaryotic HJ resolvases exhibit additional DNA debranching activities on DNA flap structures and DNA three-way junctions that are similar to RFs. Moreover, their actions are tightly regulated by post-translational modifications, protein–protein interactions and nucleocytoplasmic shuttling [70].…”

Section: Structure-specific Endonucleases: Substrate Spectrum Andmentioning

confidence: 99%

Structure-Specific Endonucleases and the Resolution of Chromosome Underreplication

Falquet

Rass

2019

Genes

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Complete genome duplication in every cell cycle is fundamental for genome stability and cell survival. However, chromosome replication is frequently challenged by obstacles that impede DNA replication fork (RF) progression, which subsequently causes replication stress (RS). Cells have evolved pathways of RF protection and restart that mitigate the consequences of RS and promote the completion of DNA synthesis prior to mitotic chromosome segregation. If there is entry into mitosis with underreplicated chromosomes, this results in sister-chromatid entanglements, chromosome breakage and rearrangements and aneuploidy in daughter cells. Here, we focus on the resolution of persistent replication intermediates by the structure-specific endonucleases (SSEs) MUS81, SLX1-SLX4 and GEN1. Their actions and a recently discovered pathway of mitotic DNA repair synthesis have emerged as important facilitators of replication completion and sister chromatid detachment in mitosis. As RS is induced by oncogene activation and is a common feature of cancer cells, any advances in our understanding of the molecular mechanisms related to chromosome underreplication have important biomedical implications.

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Regulation of Structure-Specific Endonucleases in Replication Stress

Cited by 12 publications

References 160 publications

Transcription-induced formation of extrachromosomal DNA during yeast ageing

Transcription-induced formation of extrachromosomal DNA during yeast ageing

CRL4Cdt2 ubiquitin ligase regulates Dna2 and Rad16 (XPF) nucleases by targeting Pxd1 for degradation

Structure-Specific Endonucleases and the Resolution of Chromosome Underreplication

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