Prolyl Isomerase PIN1 Regulates DNA Double-Strand Break Repair by Counteracting DNA End Resection

Steger, Martin; Murina, Olga; Hühn, D; Ferretti, Lorenza P.; Walser, Reto; Hänggi, Kay; Lafranchi, Lorenzo; Neugebauer, Christine; Paliwal, Shreya; Janscak, Pavel; Gerrits, Bertran; Sal, Giannino Del; Zerbe, Oliver; Sartori, Alessandro A.

doi:10.1016/j.molcel.2013.03.023

Cited by 79 publications

(105 citation statements)

References 52 publications

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“…Pin1 isomerizes CtIP and promotes its ubiquitylation and degradation. CtIP phosphor-mutant expression promotes the hyper-resection of DNA double-strand breaks, supporting the notion that Pin1-dependent CtIP isomerization is a key regulatory mechanism that restricts the resection of DNA double-strand breaks in late S/G2 phase [79].…”

Section: Pin1 Regulates Lipid Kinase Ubiquitin E3 Ligase and Dna Endsupporting

confidence: 64%

Prolyl isomerase Pin1 in cancer

2014

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Proline-directed phosphorylation is a posttranslational modification that is instrumental in regulating signaling from the plasma membrane to the nucleus, and its dysregulation contributes to cancer development. Protein interacting with never in mitosis A1 (Pin1), which is overexpressed in many types of cancer, isomerizes specific phosphorylated Ser/Thr-Pro bonds in many substrate proteins, including glycolytic enzyme, protein kinases, protein phosphatases, methyltransferase, lipid kinase, ubiquitin E3 ligase, DNA endonuclease, RNA polymerase, and transcription activators and regulators. This Pin1-mediated isomerization alters the structures and activities of these proteins, thereby regulating cell metabolism, cell mobility, cell cycle progression, cell proliferation, cell survival, apoptosis and tumor development.

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Section: Pin1 Regulates Lipid Kinase Ubiquitin E3 Ligase and Dna Endsupporting

confidence: 64%

Prolyl isomerase Pin1 in cancer

2014

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“…CtIP plays a role in DSB resection very similar to that of Sae2 in budding yeast and is already known to be modified by CDK and by ATM/ATR (44). Interestingly, the prolyl isomerase Pin1 was shown to regulate the degradation of CtIP through ubiquitination in human cells (45), but it is unknown whether a similar relationship might exist with Sae2 in budding yeast. The example shown in this study with Sae2 may be a model for many other enzymes in the DNA damage response or in other cellular processes, where the availability of a protein is controlled reversibly at the posttranslational level by altering its oligomeric state.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-Regulated Transitions in an Oligomeric State Control the Activity of the Sae2 DNA Repair Enzyme

Chow

Bernstein

et al. 2014

Molecular and Cellular Biology

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In the DNA damage response, many repair and signaling molecules mobilize rapidly at the sites of DNA double-strand breaks. This network of immediate responses is regulated at the level of posttranslational modifications that control the activation of DNA processing enzymes, protein kinases, and scaffold proteins to coordinate DNA repair and checkpoint signaling. Here we investigated the DNA damage-induced oligomeric transitions of the Sae2 protein, an important enzyme in the initiation of DNA double-strand break repair. Sae2 is a target of multiple phosphorylation events, which we identified and characterized in vivo in the budding yeast Saccharomyces cerevisiae. Both cell cycle-dependent and DNA damage-dependent phosphorylation sites in Sae2 are important for the survival of DNA damage, and the cell cycle-regulated modifications are required to prime the damagedependent events. We found that Sae2 exists in the form of inactive oligomers that are transiently released into smaller active units by this series of phosphorylations. DNA damage also triggers removal of Sae2 through autophagy and proteasomal degradation, ensuring that active Sae2 is present only transiently in cells. Overall, this analysis provides evidence for a novel type of protein regulation where the activity of an enzyme is controlled dynamically by posttranslational modifications that regulate its solubility and oligomeric state.

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“…CtIP knockout (KO) mice is embryonic lethal, and CtIP is essential for suppressing genome aberration (136,137). CtIP/ Sae2 is also highly regulated by posttranslational modifications, including phosphorylation (138-141), acetylation (142,143), ubiquitination (both proteolytic and nonproteolytic) (144)(145)(146)(147), and deregulation of these processes lead to DSB repair deficiency, evidence that the DSB end resection is subject to a dynamic regulation.…”

Section: Dubs That Modulate Dsb Repair Signalingmentioning

confidence: 99%

Role of Deubiquitinating Enzymes in DNA Repair

Kee

Huang

2016

Molecular and Cellular Biology

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Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling. DEUBIQUITINATING ENZYMES Safeguarding the genome from genotoxic stress is critical for cell survival and for preventing various human diseases, including cancer. DNA repair or DNA damage responses are under exquisite control and must be accurately and rapidly executed when genome integrity is challenged. Understanding the molecular mechanisms and regulation of critical DNA repair and damage response factors in mammalian cells will provide insight into the pathogenesis of human diseases and aid in the development of therapeutics. Ubiquitination is a posttranslational modification event that allows for rapid and dynamic changes in a protein fate or function. The ubiquitin-proteasome system (UPS) is an essential posttranslational regulatory mechanism that permeates into diverse biological processes, including the DNA repair and damage response pathways. While the role of ubiquitin in mediating controlled degradation/proteolysis of specific proteins is well established, nonproteolytic functions of ubiquitination have also emerged as important players in signaling pathways that often exist in parallel with the UPS. Deubiquitinating enzymes (DUBs), responsible for reversing the ubiquitination reaction by removing covalently attached ubiquitin molecules from substrates or polyubiquitinated chains, have recently exploded onto the ubiquitin field as key regulators of both the UPS and of the nonproteolytic functions of ubiquitination. Thus, DUBs exert profound influence on many cellular pathways, including one of the best-studied biological processes involving DNA repair and damage response in mammalian cells.There are approximately 95 DUBs encoded by the human genome, which fall into one of the five subclasses: ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), Machado-Joseph domain-containing proteins (MJDs), Otubain domain-containing proteases (OTUs), and JAMM (JAB1/MPN/ Mov34) proteases (1, 2). Ubiquitin has seven internal lysine residues (Lys6,, each providing sites for the generation of an isopeptide bond with the carboxy terminus of another ubiquitin to form ubiquitin polymers, otherwise known as polyubiquitination. Linear ubiquitin chains can also be generated when the amino-terminal methionine (Met) of ubiquitin (Met1) forms a peptide bond with the carboxy-terminal glycine (Gly) of ubiquitin. As different types of polyubiquitin polymers adopt different conformations (3), it is not surprising that many DUBs show some degree of specificity toward differentially linked polyubiquitination, each of which results in a different physi...

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Prolyl Isomerase PIN1 Regulates DNA Double-Strand Break Repair by Counteracting DNA End Resection

Cited by 79 publications

References 52 publications

Prolyl isomerase Pin1 in cancer

Prolyl isomerase Pin1 in cancer

Phosphorylation-Regulated Transitions in an Oligomeric State Control the Activity of the Sae2 DNA Repair Enzyme

Role of Deubiquitinating Enzymes in DNA Repair

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