Dynamic regulation of Pif1 acetylation is crucial to the maintenance of genome stability

Ononye, Onyekachi E.; Sausen, Christopher W.; Bochman, Matthew L.; Balakrishnan, Lata

doi:10.1007/s00294-020-01116-5

Cited by 7 publications

(4 citation statements)

References 73 publications

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“…At this time, regulation of Cdc13 activities appears to be controlled by a complex set of PTMs, primarily phosphorylation events, occurring on Cdc13, Stn1, and Pif1 ( 32 , 38 , 89 , 90 ). Other modifications such as SUMOylation of Cdc13 and acetylation of Pif1 offer additional regulatory mechanisms ( 42 , 91 , 92 ). Cdc13 also plays a role in telomere addition at DSBs where the interaction of Pif1 and/or Hrq1 may be crucial for removing Cdc13 to avoid telomere addition to DSBs ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

Cdc13 exhibits dynamic DNA strand exchange in the presence of telomeric DNA

Nickens,

Feng,

Shen

et al. 2024

Nucleic Acids Research

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Telomerase is the enzyme that lengthens telomeres and is tightly regulated by a variety of means to maintain genome integrity. Several DNA helicases function at telomeres, and we previously found that the Saccharomyces cerevisiae helicases Hrq1 and Pif1 directly regulate telomerase. To extend these findings, we are investigating the interplay between helicases, single-stranded DNA (ssDNA) binding proteins (ssBPs), and telomerase. The yeast ssBPs Cdc13 and RPA differentially affect Hrq1 and Pif1 helicase activity, and experiments to measure helicase disruption of Cdc13/ssDNA complexes instead revealed that Cdc13 can exchange between substrates. Although other ssBPs display dynamic binding, this was unexpected with Cdc13 due to the reported in vitro stability of the Cdc13/telomeric ssDNA complex. We found that the DNA exchange by Cdc13 occurs rapidly at physiological temperatures, requires telomeric repeat sequence DNA, and is affected by ssDNA length. Cdc13 truncations revealed that the low-affinity binding site (OB1), which is distal from the high-affinity binding site (OB3), is required for this intermolecular dynamic DNA exchange (DDE). We hypothesize that DDE by Cdc13 is the basis for how Cdc13 ‘moves’ at telomeres to alternate between modes where it regulates telomerase activity and assists in telomere replication.

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Section: Discussionmentioning

confidence: 99%

Cdc13 exhibits dynamic DNA strand exchange in the presence of telomeric DNA

Nickens,

Feng,

Shen

et al. 2024

Nucleic Acids Research

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“…Transcriptome analysis revealed a P3C-induced downregulation of the PIF1 helicase gene that maintains nuclear and mitochondrial DNA integrity in eukaryotes [ 87 ]. PIF1 downregulation could be associated with the mitochondrial damage leading to its depolarization and the nuclear DNA fragmentation detected during the cell cycle in vitro analyses ( Figure 4 B and Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways

Gutierrez

Contreras

Villanueva

et al. 2022

Cells

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In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.

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“…At this time, regulation of Cdc13 activities appears to be controlled by a complex set of PTMs, primarily phosphorylation events, occurring on Cdc13, Stn1, and Pif1 (12,18,78,79). Other modifications such as SUMOylation of Cdc13 and acetylation of Pif1 offer additional regulatory mechanisms (23,80,81). Cdc13 also plays a role in telomere addition at DSBs where the interaction of Pif1 and/or Hrq1 may be crucial for removing Cdc13 to avoid telomere addition to DSBs (45).…”

Section: Model For Cdc13 Dde In Vivomentioning

confidence: 99%

Cdc13 exhibits dynamic DNA strand exchange in the presence of telomeric DNA

Nickens,

Feng,

Shen

et al. 2023

Preprint

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Telomerase is the enzyme that lengthens telomeres and is tightly regulated by a variety of means to maintain genome integrity. Several DNA helicases function at telomeres, and we previously found that theSaccharomyces cerevisiaehelicases Hrq1 and Pif1 directly regulate telomerase. To extend these findings, we are investigating the interplay between helicases, single-stranded DNA (ssDNA) binding proteins (ssBPs), and telomerase. The yeast ssBPs Cdc13 and RPA differentially affect Hrq1 and Pif1 helicase activity, and experiments to measure helicase disruption of Cdc13/ssDNA complexes instead revealed that Cdc13 can exchange between substrates. Although other ssBPs display dynamic binding, this was unexpected with Cdc13 due to the reportedin vitrostability of the Cdc13/telomeric ssDNA complex. We found that the DNA exchange by Cdc13 occurs rapidly at physiological temperatures, requires telomeric repeat sequence DNA, and is affected by ssDNA length. Cdc13 truncations revealed that the low-affinity binding site (OB1), which is distal from the high-affinity binding site (OB3), is required for this intermolecular dynamic DNA exchange (DDE). We hypothesize that DDE by Cdc13 is the basis for how Cdc13 “moves” at telomeres to alternate between modes where it regulates telomerase activity and assists in telomere replication.

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Dynamic regulation of Pif1 acetylation is crucial to the maintenance of genome stability

Cited by 7 publications

References 73 publications

Cdc13 exhibits dynamic DNA strand exchange in the presence of telomeric DNA

Cdc13 exhibits dynamic DNA strand exchange in the presence of telomeric DNA

Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways

Cdc13 exhibits dynamic DNA strand exchange in the presence of telomeric DNA

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