The Tousled-Like Kinases as Guardians of Genome Integrity

Benedetti, Arrigo De

doi:10.5402/2012/627596

Cited by 27 publications

(37 citation statements)

References 91 publications

(157 reference statements)

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“…40 As a kinase, TLK functions by phosphorylating its target proteins, such as the chromatin assembly factor ASF1 and Rad9. 40 In the Drosophila loss-of-function tlk mutant, nuclear divisions are arrested at interphase, and cells eventually undergo apoptosis. 34 Therefore, loss-of-function tlk should reduce cell numbers.…”

Section: Discussionmentioning

confidence: 99%

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Tousled-like kinase mediated a new type of cell death pathway in Drosophila

et al. 2015

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Programmed cell death (PCD) has an important role in sculpting organisms during development. However, much remains to be learned about the molecular mechanism of PCD. We found that ectopic expression of tousled-like kinase (tlk) in Drosophila initiated a new type of cell death. Furthermore, the TLK-induced cell death is likely to be independent of the canonical caspase pathway and other known caspase-independent pathways. Genetically, atg2 RNAi could rescue the TLK-induced cell death, and this function of atg2 was likely distinct from its role in autophagy. In the developing retina, loss of tlk resulted in reduced PCD in the interommatidial cells (IOCs). Similarly, an increased number of IOCs was present in the atg2 deletion mutant clones. However, double knockdown of tlk and atg2 by RNAi did not have a synergistic effect. These results suggested that ATG2 may function downstream of TLK. In addition to a role in development, tlk and atg2 RNAi could rescue calcium overload-induced cell death. Together, our results suggest that TLK mediates a new type of cell death pathway that occurs in both development and calcium cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

“…40 In Drosophila, TLK phosphorylates ASF1 and causes nuclear division arrest and pupal lethality. 34 Our result showed that asf1 RNAi had no effect on the TLK-induced cell death Figure 4E), suggesting that the function of TLK on cell death was likely different from its role in chromatin organization.…”

Section: Figure 2 (Continued)mentioning

confidence: 99%

Tousled-like kinase mediated a new type of cell death pathway in Drosophila

et al. 2015

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“…Another possibility is that the absence of this interaction may be a result of fundamental differences between budding yeast and mammalian cells in the mechanism of DNA damage checkpoint regulation. However, Asf1 has been shown to participate in nucleosome deposition following repair (Mello et al 2002) and interact with tousled-like kinases (TLKs), a family of kinases specific to metazoans that plays an extensive role in the regulation of replication, transcription, and repair (Groth et al 2003(Groth et al , 2005Mousson et al 2007;De Benedetti 2012). These observations implicate Asf1 with regulation of the DNA damage checkpoint in mammalian cells as well.…”

Section: Asf1 Facilitates Rad53 Dephosphorylationmentioning

confidence: 95%

Asf1 facilitates dephosphorylation of Rad53 after DNA double-strand break repair

et al. 2016

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To allow for sufficient time to repair DNA double-stranded breaks (DSBs), eukaryotic cells activate the DNA damage checkpoint. In budding yeast, Rad53 (mammalian Chk2) phosphorylation parallels the persistence of the unrepaired DSB and is extinguished when repair is complete in a process termed recovery or when the cells adapt to the DNA damage checkpoint. A strain containing a slowly repaired DSB does not require the histone chaperone Asf1 to resume cell cycle progression after DSB repair. When a second, rapidly repairable DSB is added to this strain, Asf1 becomes required for recovery. Recovery from two repairable DSBs also depends on the histone acetyltransferase Rtt109 and the cullin subunit Rtt101, both of which modify histone H3 that is associated with Asf1. We show that dissociation of histone H3 from Asf1 is required for efficient recovery and that Asf1 is required for complete dephosphorylation of Rad53 when the upstream DNA damage checkpoint signaling is turned off. Our data suggest that the requirements for recovery from the DNA damage checkpoint become more stringent with increased levels of damage and that Asf1 plays a histone chaperone-independent role in facilitating complete Rad53 dephosphorylation following repair.

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“…There is a curve inflection following the second dose of doxo for both groups (+/-THD), and considering that the dose and schedule of doxo administration was not fully optimized, we concluded that perhaps a more quantitative model (MDA-231-Luc cells) to more precisely measure tumor growth could yield more definitive results. In any case, the tumors were excised at the end of the experiment (before the control group tumors reached the preset end point of 1,500 mm 3 ) and processed for immunohistochemistry (IHC) analysis. The mice were dosed on the last day before euthanasia with doxo to induce bona fide DSBs.…”

Section: Animal Studiesmentioning

confidence: 99%

“…3 Two TLK genes (TLK1 and TLK2) with several splice variants were identified in humans. TLK1/1B interacts specifically with the chromatin assembly factor Asf1 and Rad9, [4][5][6] and we have presented evidence that TLK1B promotes repair by processing the double-strand break (DSB) ends and disassembling chromatin nearby to facilitate the recruitment of repair proteins.…”

Section: Introductionmentioning

confidence: 99%

Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy

et al. 2013

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The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 and Rad9, regulating double-strand break (DSB) repair and the DNA damage response (DDR). TLKs maintain genomic stability and are important therapeutic intervention targets. We identified specific inhibitors of TLKs from several compound libraries, some of which belong to the family of phenothiazine antipsychotics. The inhibitors prevented the TLK-mediated phosphorylation of Rad9(S328) and impaired checkpoint recovery and DSB repair. The inhibitor thioridazine (THD) potentiated tumor killing with chemotherapy and also had activity alone. Staining for γ-H2AX revealed few positive cells in untreated tumors, but large numbers in mice treated with low doxorubicin or THD alone, possibly the result of the accumulation of DSBs that are not promptly repaired as they may occur in the harsh tumor growth environment.

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The Tousled-Like Kinases as Guardians of Genome Integrity

Cited by 27 publications

References 91 publications

Tousled-like kinase mediated a new type of cell death pathway in Drosophila

Tousled-like kinase mediated a new type of cell death pathway in Drosophila

Asf1 facilitates dephosphorylation of Rad53 after DNA double-strand break repair

Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy

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