Exonuclease 1 and its versatile roles in DNA repair

Keijzers, Guido; Liu, Dekang; Rasmussen, Lene Juel

doi:10.1080/10409238.2016.1215407

Cited by 58 publications

(54 citation statements)

References 115 publications

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“…52, 53 Another important mediator, EXO1 is involved in cell cycle and MMR, which have a role in telomere maintenance and proliferative capacity of stem cells. 54 Our RT-PCR results verified the lower expression of CCNA2 , MCM6 , RAD21 , EXO1 and STAG1 in P3 BMSCs compared with BMMNCs, indicating that expansion may alter telomerase activity and chromosomal stability of MSCs, leading to impaired stemness and multipotency. Many studies have demonstrated absence of telomerase activity in human MSCs.…”

Section: Discussionsupporting

confidence: 74%

In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

et al. 2017

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In vitro cultured autologous mesenchymal stem cells (MSCs) within passage 5 have been approved for clinical application in stem cell-based treatment of cartilage defects. However, their chondrogenic potential has not yet been questioned or verified. In this study, the chondrogenic potential of bone marrow MSCs at passage 3 (P3 BMSCs) was investigated both in cartilage repair and in vitro, with freshly isolated bone marrow mononuclear cells (BMMNCs) as controls. The results showed that P3 BMSCs were inferior to BMMNCs not only in their chondrogenic differentiation ability but also as candidates for long-term repair of cartilage defects. Compared with BMMNCs, P3 BMSCs presented a decay in telomerase activity and a change in chromosomal morphology with potential anomalous karyotypes, indicating senescence. In addition, interindividual variability in P3 BMSCs is much higher than in BMMNCs, demonstrating genomic instability. Interestingly, remarkable downregulation in cell cycle, DNA replication and mismatch repair (MMR) pathways as well as in multiple genes associated with telomerase activity and chromosomal stability were found in P3 BMSCs. This result indicates that telomerase and chromosome anomalies might originate from expansion, leading to impaired stemness and pluripotency of stem cells. In vitro culture and expansion are not recommended for cell-based therapy, and fresh BMMNCs are the first choice.

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Section: Discussionsupporting

confidence: 74%

In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

et al. 2017

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“…However, how resection is restrained or terminated is not well understood. Our results uncover a novel mechanism by which resection is negatively regulated via the degradation of EXO1, an exonuclease with critical functions in long-range resection (25,26). Our results indicate that EXO1, although vital for resection and HR, is rapidly degraded after DNA damage in a phosphorylation-and ubiquitination-dependent manner.…”

Section: Discussionmentioning

confidence: 72%

“…EXO1 is a 5Ј to 3Ј exonuclease with key roles in DNA mismatch repair, mitotic and meiotic recombination, replication, and telomere homeo-stasis (for review, see Refs. [25][26][27]. Research from our laboratory has established that EXO1 plays a major role in DNA end resection in human cells and not only promotes a switch from NHEJ to HR but also facilitates a transition from ATM-to ATRmediated checkpoint signaling (15,16,23,28,29).…”

mentioning

confidence: 99%

DNA-damage-induced degradation of EXO1 exonuclease limits DNA end resection to ensure accurate DNA repair

Tomimatsu

Mukherjee

Harris

et al. 2017

Journal of Biological Chemistry

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End resection of DNA double-strand breaks (DSBs) to generate 3'-single-stranded DNA facilitates DSB repair via error-free homologous recombination (HR) while stymieing repair by the error-prone non-homologous end joining (NHEJ) pathway. Activation of DNA end resection involves phosphorylation of the 5' to 3' exonuclease EXO1 by the phosphoinositide 3-kinase-like kinases ATM (ataxia telangiectasia-mutated) and ATR (ATM and Rad3-related) and by the cyclin-dependent kinases 1 and 2. After activation, EXO1 must also be restrained to prevent over-resection that is known to hamper optimal HR and trigger global genomic instability. However, mechanisms by which EXO1 is restrained are still unclear. Here, we report that EXO1 is rapidly degraded by the ubiquitin-proteasome system soon after DSB induction in human cells. ATR inhibition attenuated DNA-damage-induced EXO1 degradation, indicating that ATR-mediated phosphorylation of EXO1 targets it for degradation. In accord with these results, EXO1 became resistant to degradation when its SQ motifs required for ATR-mediated phosphorylation were mutated. We show that upon the induction of DNA damage, EXO1 is ubiquitinated by a member of the Skp1-Cullin1-F-box (SCF) family of ubiquitin ligases in a phosphorylation-dependent manner. Importantly, expression of degradation-resistant EXO1 resulted in hyper-resection, which attenuated both NHEJ and HR and severely compromised DSB repair resulting in chromosomal instability. These findings indicate that the coupling of EXO1 activation with its eventual degradation is a timing mechanism that limits the extent of DNA end resection for accurate DNA repair.

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“…Exo1 promotes recombination by catalyzing 5´ to 3´ DNA strand resection (Keijzers et al, 2016), and its loss results in a ~2.5 fold reduction in gene conversions, and a ~2 fold reduction in deletions, in strains with RTS1 -AO and no additional DNA spacer (Figure 4A) (Osman et al, 2016). Its loss also causes a similar reduction in gene conversions (~2.2 fold) when the centromere-proximal 5 kb spacer is added (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Inter-Fork Strand Annealing causes genomic deletions during the termination of DNA replication

Morrow

Nguyen

Fower

et al. 2017

eLife

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Problems that arise during DNA replication can drive genomic alterations that are instrumental in the development of cancers and many human genetic disorders. Replication fork barriers are a commonly encountered problem, which can cause fork collapse and act as hotspots for replication termination. Collapsed forks can be rescued by homologous recombination, which restarts replication. However, replication restart is relatively slow and, therefore, replication termination may frequently occur by an active fork converging on a collapsed fork. We find that this type of non-canonical fork convergence in fission yeast is prone to trigger deletions between repetitive DNA sequences via a mechanism we call Inter-Fork Strand Annealing (IFSA) that depends on the recombination proteins Rad52, Exo1 and Mus81, and is countered by the FANCM-related DNA helicase Fml1. Based on our findings, we propose that IFSA is a potential threat to genomic stability in eukaryotes.DOI: http://dx.doi.org/10.7554/eLife.25490.001

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Exonuclease 1 and its versatile roles in DNA repair

Cited by 58 publications

References 115 publications

In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

DNA-damage-induced degradation of EXO1 exonuclease limits DNA end resection to ensure accurate DNA repair

Inter-Fork Strand Annealing causes genomic deletions during the termination of DNA replication

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