Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress

Mathew, Veena; Tam, Annie; Milbury, Karissa L.; Hofmann, Analise; Hughes, Christopher S.; Morin, Gregg B.; Loewen, Christopher; Stirling, Peter C.

doi:10.1083/jcb.201612018

Cited by 13 publications

(35 citation statements)

References 51 publications

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“…In a concerted effort to maintain genome integrity, the DDR pathway plays a critical role in sensing DNA damage and orchestrating the repair of ensuing DNA lesions [75–77]. This recovery process typically involves global remodeling of both the transcriptome and the proteome [78–80]. However, an implicit assumption in this thinking is that most cells return to their initial transcriptional and proteomic state following DNA damage and repair, aside from those that may acquire a mutation.…”

Section: Introductionmentioning

confidence: 99%

Mutations, protein homeostasis, and epigenetic control of genome integrity

Xie

Jarosz

2018

DNA Repair

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From bacteria to humans, ancient stress responses enable organisms to contend with damage to both the genome and the proteome. These pathways have long been viewed as fundamentally separate responses. Yet recent discoveries from multiple fields have revealed surprising links between the two. Many DNA-damaging agents also target proteins, and mutagenesis induced by DNA damage produces variant proteins that are prone to misfolding, degradation, and aggregation. Likewise, recent studies have observed pervasive engagement of a p53-mediated response, and other factors linked to maintenance of genomic integrity, in response to misfolded protein stress. Perhaps most remarkably, protein aggregation and self-assembly has now been observed in multiple proteins that regulate the DNA damage response. The importance of these connections is highlighted by disease models of both cancer and neurodegeneration, in which compromised DNA repair machinery leads to profound defects in protein quality control, and vice versa.

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Section: Introductionmentioning

confidence: 99%

Mutations, protein homeostasis, and epigenetic control of genome integrity

Xie

Jarosz

2018

DNA Repair

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“…INQ formation is driven by the small heat shock protein Hsp42, and the aggregase protein Btn2 (13), while INQ dissolution is regulated by Hsp104 and the Hsp70 system (9,11,12). Here we show that Cdc48 is also a stress-inducible component on INQ structures and that it plays an enzymatic role in INQ turnover.…”

Section: Introductionmentioning

confidence: 69%

Cdc48 regulates intranuclear quality control sequestration of the Hsh155 splicing factor

Mathew

Kumar

Jiang

et al. 2020

Preprint

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Cdc48/VCP is a highly conserved ATPase chaperone that plays an essential role in the assembly or disassembly of protein-DNA complexes and in degradation of misfolded proteins. We find that Cdc48 accumulates during cellular stress at intranuclear protein quality control (INQ) sites. Cdc48 function is required to suppress INQ formation under non-stress conditions and to promote recovery following genotoxic stress. Cdc48 physically associates with the INQ substrate and splicing factor Hsh155 and regulates its assembly with partner proteins. Accordingly, cdc48 mutants have defects in splicing and show spontaneous distribution of Hsh155 to INQ aggregates where it is stabilized. Overall, this study shows that Cdc48 regulates deposition of proteins at INQ and suggests a previously unknown role for Cdc48 in the regulation or stability of splicing subcomplexes.

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“…Sfp1 is well characterized for its role in adjusting cell size and ribosome production during stress 53–55,76,77 , yet its functions outside the control of ribosome biogenesis are understudied. Recently, Matthew et al found that sequestration of the splicing factor Hsh155 during genotoxic stress was regulated via TORC1 signaling through Sfp1 93 . Together with our data showing that Sfp1 regulates TRA1 expression, this study supports an expanded role for Sfp1 in stress response, beyond regulating ribosome biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae

Jiang

Berg

Genereaux

et al. 2018

Preprint

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Proteotoxic stress triggers transcriptional responses that allow cells to compensate for the accumulation of toxic misfolded proteins. Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington’s disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co-activator complexes and is linked to multiple cellular processes associated with misfolded protein stress, including the heat shock response. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model of HD to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins, mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins also upregulated the expression of TRA1 and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effector SFP1 specifically abolished upregulation of TRA1 upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of Tra1, linking TORC1 and cell growth regulation to functions of the SAGA acetyltransferase complex during misfolded protein stress.

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Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress

Cited by 13 publications

References 51 publications

Mutations, protein homeostasis, and epigenetic control of genome integrity

Mutations, protein homeostasis, and epigenetic control of genome integrity

Cdc48 regulates intranuclear quality control sequestration of the Hsh155 splicing factor

Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae

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