The ATM- and ATR-related SCD domain is over-represented in proteins involved in nervous system development

Cara, Lukas R.; Baitemirova, Medina; Follis, Jack L.; Larios‐Sanz, Maia; Ribes-Zamora, Albert

doi:10.1038/srep19050

Cited by 17 publications

(18 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, anti-ATR immunogold labeling decorates ATR on actin filaments (Kidiyoor and Foiani, personal communication). This is consistent with a recent finding that actin cytoskeleton and actin-binding proteins often contain clusters of S/TQ motifs in a SCD domain, and SCD domain proteins interact with ATR or ATM 55 . A recent study by Mullins et al indicates that DNA damage induces the assembly of nuclear actin that is required for efficient clearance of double-strand breaks 34 .…”

Section: Discussionsupporting

confidence: 93%

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling

et al. 2017

View full text Add to dashboard Cite

Phosphoinositide lipids (PPIs) are enriched in the nucleus and are accumulated at DNA damage sites. Here, we investigate roles of nuclear PPIs in DNA damage response by sequestering specific PPIs with the expression of nuclear-targeted PH domains, which inhibits recruitment of Ataxia telangiectasia and Rad3-related protein (ATR) and reduces activation of Chk1. PPI-binding domains rapidly (< 1 s) accumulate at damage sites with local enrichment of PPIs. Accumulation of PIP3 in complex with the nuclear receptor protein, SF1, at damage sites requires phosphorylation by inositol polyphosphate multikinase (IPMK) and promotes nuclear actin assembly that is required for ATR recruitment. Suppressed ATR recruitment/activation is confirmed with latrunculin A and wortmannin treatment as well as IPMK or SF1 depletion. Other DNA repair pathways involving ATM and DNA-PKcs are unaffected by PPI sequestration. Together, these findings reveal that nuclear PPI metabolism mediates an early damage response through the IPMK-dependent pathway to specifically recruit ATR.

show abstract

Section: Discussionsupporting

confidence: 93%

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Activation of Ssk2 mediates actin cytoskeleton recovery from osmotic stress (61). Accordingly, our results are in agreement with an intriguing hypothesis that SCDs may possess broad and overarching roles in eukaryotic cells given that in S. cerevisiae and mammals there is an unexpected abundance of SCD-containing proteins belonging to functional regimes not related to DDR, such as endocytosis, microtubules, and actin cytoskeleton, as well as in pathways related to nervous system development (17,62). Thus, we suggest that these IDRs are versatile toolkits for functional divergence in signaling and evolution.…”

Section: Discussionsupporting

confidence: 88%

“…Intriguingly, the vps64D mutant shows increased aneuploidy tolerance (58). Kel1 cytoskeleton, as well as in pathways related to nervous system development (17,62). Thus, we suggest that these IDRs are versatile toolkits for functional divergence in signaling and evolution.…”

Section: Discussionmentioning

confidence: 80%

Noncanonical usage of stop codons in ciliates expands proteins with Q-rich motifs

Chuang

Woo

Tsai

et al. 2020

Preprint

View full text Add to dashboard Cite

Intrinsically disordered regions (IDRs) are protein sequences lacking fixed or ordered three-dimensional structures. Many IDRs are endowed with important molecular functions such as physical interactions, posttranslational modifications or solubility enhancement. We reveal that several biologically important IDRs can act as N-terminal fusion carriers to promote target protein folding or protein quality control, thereby enhancing protein expression. This nanny function has a reasonably strong correlation with high S/T/Q/N amino acid content in IDRs and it is tunable (e.g., via phosphorylation) to regulate protein homeostasis. We propose a hypothesis that “N-terminal intrinsic disorder facilitates abundance” (NIDFA) to explain how some yeast proteins use their N-terminal IDRs (N-IDRs) to generate high levels of protein product. These N-IDRs are versatile toolkits for functional divergence in signaling and evolution.SignificanceDisorder within an otherwise well-structured protein is mostly found in intrinsically disordered regions (IDRs). IDRs can provide many advantages to proteins, including: (1) mediating protein-protein or protein-peptide interactions by adopting different conformations; (2) facilitating protein regulation via diverse posttranslational modifications; and (3) regulating the half-lives of proteins that have been targeted for proteasomal degradation. Here, we report that several biologically important IDRs in S. cerevisiae can act as N-terminal fusion carriers to promote target protein folding or protein quality control, thereby enhancing protein expression. We demonstrate by genetic and bioinformatic analyses that this nanny function is well correlated with high content of serine, threonine, glutamine and asparagine in IDRs and is tunable (e.g., via phosphorylation) to regulate protein homeostasis.

show abstract

“…Most of the known ATM substrates responsible for cell cycle control and DNA repair contain a number of SCDs (Table 2). We therefore searched for SCDs in myelin proteins, common OL markers as well as OL-associated transcription factors using SCDFinder [74]. Both mouse MBP and MyRF were identified as having relatively high concentration of SCDs ( Table 2).…”

Section: Myelin and Ol Related Proteins Rich In S/tq Motifs Are Putatmentioning

confidence: 99%

Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes

Tse

Cheng

et al. 2021

Preprint

View full text Add to dashboard Cite

Ataxia-telangiectasia (A-T) is a rare genetic disease caused by mutations in the gene encoding the ATM (Ataxia-telangiectasia mutated) protein. Although neuronal degeneration in the cerebellum remains the most prominent sign in A-T, neuroimaging studies reveal myelin abnormalities as early comorbidities. We hypothesize that these myelin defects are the direct consequence of ATM deficiencies in the oligodendrocytes (OL) lineage. We examined samples from ten A-T brains in which the ATM mutations had been mapped by targeted genomic sequencing as well as samples from Atm-/- mice. In healthy human and wild type mouse cerebellum we confirmed the presence of ATM in white matter OLs. In A-T but not age-matched controls, a significant reduction in OL density was coupled with a massive astrogliosis. We found that the extent of this OL pathology was particularly strong in cases with frameshifts or premature termination ATM mutations. Similar pathologies were also found in Atm-/- mice in an age- and gene dose-dependent fashion. In vitro, DNA damage induced by etoposide-induced DSBs or blockade of ATM activity with KU-60019 differentially jeopardized cell cycle control in OL progenitors and mature OLs. Turning to structural analysis in silico, we identified likely interactions between ATM and myelin basic protein as well as myelin regulatory factor and confirm this by immunoprecipitation. These novel OL-specific functions of the ATM protein affect all stages of the OL lineage. They thus provide a cell biological basis for a direct role for ATM in central nervous system myelination and illustrate how the myelin pathology found in A-T is at least in part independent of neuronal degeneration.

show abstract

The ATM- and ATR-related SCD domain is over-represented in proteins involved in nervous system development

Cited by 17 publications

References 55 publications

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling

DNA damage causes rapid accumulation of phosphoinositides for ATR signaling

Noncanonical usage of stop codons in ciliates expands proteins with Q-rich motifs

Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes

Contact Info

Product

Resources

About