Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

Lee, Ji-Hoon; Ryu, Seung Woo; Ender, Nicolette A.; Paull, Tanya T.

doi:10.1016/j.molcel.2021.01.019

Cited by 43 publications

(68 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found only 38 proteins that aggregated less in ATM KO cells, while 171 proteins aggregated significantly more. Of these 171 proteins, 91 were also found to aggregate more in ATM -depleted U2OS cells in a recent study by Lee et al (Lee et al 2021). Similar to the CPT-induced aggregation in HEK293T cells, proteins that aggregate more in U2OS ATM KO cells appear to be largely soluble in wild-type cells, but now aggregate highly consistently (Figure 2 – figure supplement 1E).…”

Section: Resultsmentioning

confidence: 86%

Section: Camptothecin and Atm Loss Drive Aggregation Similarly In A Cell-type Dependent Mannermentioning

confidence: 86%

“…The characteristics and relevance of the aggregation induced by a loss of ATM are still largely unclear. Loss of MRE11 has recently also been found to result in protein aggregation (Lee et al 2021), and since MRE11 and ATM function in the same DDR pathway, this raises the question whether other genotoxic conditions can challenge protein homeostasis as well (Ainslie et al 2021; Huiting and Bergink 2021).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Huiting

et al. 2021

Preprint

View full text Add to dashboard Cite

A loss of the checkpoint kinase ATM leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and a high risk to cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases result in a similar, widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including Huntingtin exon1 containing an expanded polyglutamine repeat, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a potent suppressor of it. Our findings reveal that various genotoxic conditions trigger widespread protein aggregation in a manner that is highly reminiscent of the aggregation occurring in situations of proteotoxic stress and in proteinopathies.

show abstract

Section: Resultsmentioning

confidence: 86%

Section: Camptothecin and Atm Loss Drive Aggregation Similarly In A Cell-type Dependent Mannermentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Huiting

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Of relevance for neurodegenerative disease, PAR-related protein-rich condensates were found to be wide-spread in A-T patient cerebellum (Lee et al, 2021). These findings point to an inherent danger of DNA damageassociated phase separation, particularly in the presence of excessive DNA damage or repair defects that may prevent its dynamic formation and resolution.…”

Section: Phase Separation In Neurodegenerative Diseasementioning

confidence: 93%

“…While DNA lesion-associated phase separation is emerging as an integral and dynamic aspect of the DNA damage response, recent work by Paull and colleagues suggests that PAR-seeded liquid demixing may ultimately result in insoluble protein-rich biomolecular condensates observed in the cerebellar neurodegenerative disorder associated with ataxia-telangiectasia (A-T) ( Lee et al, 2021 ) ( Figure 4B ). A-T is caused by the loss of ATM kinase, and hypomorphic mutations in the MRE11 repair factor can cause the related A-T-like disorder (ATLD), implicating a prominent role for DNA damage in disease progression ( Taylor et al, 2004 ; Regal et al, 2013 ).…”

Section: D Genome Organization-related Genome Instability In Cancer and Diseasementioning

confidence: 99%

Encounters in Three Dimensions: How Nuclear Topology Shapes Genome Integrity

2021

View full text Add to dashboard Cite

Almost 25 years ago, the phosphorylation of a chromatin component, histone H2AX, was discovered as an integral part of the DNA damage response in eukaryotes. Much has been learned since then about the control of DNA repair in the context of chromatin. Recent technical and computational advances in imaging, biophysics and deep sequencing have led to unprecedented insight into nuclear organization, highlighting the impact of three-dimensional (3D) chromatin structure and nuclear topology on DNA repair. In this review, we will describe how DNA repair processes have adjusted to and in many cases adopted these organizational features to ensure accurate lesion repair. We focus on new findings that highlight the importance of chromatin context, topologically associated domains, phase separation and DNA break mobility for the establishment of repair-conducive nuclear environments. Finally, we address the consequences of aberrant 3D genome maintenance for genome instability and disease.

show abstract