Hydroxyurea and hydroxamic acid derivatives as antitumor drugs

Šaban, Nina; Bujak, Maro

doi:10.1007/s00280-009-0991-z

Cited by 110 publications

(90 citation statements)

References 82 publications

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“…In contrast to camptothecin, hydroxyurea (HU) inactivates ribonucleotide reductase, ultimately leading to accumulation of double-stranded breaks near DNA replication forks (for review, see Saban and Bujak 2009). To evaluate the specificity of damage sensitivity and resistance, analysis was performed with HU as the drug challenge (Fig.…”

Section: Resultsmentioning

confidence: 99%

Homocitrate synthase connects amino acid metabolism to chromatin functions through Esa1 and DNA damage

Scott¹,

Pillus²

2010

Genes Dev.

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The enzyme homocitrate synthase (HCS) catalyzes the first step in lysine biosynthesis, and early biochemical data placed it in the cytoplasm or mitochondria, where most amino acid synthesis occurs. It was therefore surprising when refined fractionation techniques and specific immunoreagents clearly demonstrated its localization to the nucleus. These observations raised the question of whether HCS had a function within the nucleus independent of lysine synthesis. We demonstrate that HCS encoded by LYS20 in yeast is linked to the key process of DNA damage repair through the essential MYST family histone acetyltransferase Esa1 and the H2A.Z histone variant. This discovery indicates that HCS has a role in addition to amino acid synthesis, and that it functions in nuclear activities involving chromatin regulation that are distinct from its previously established role in lysine biosynthesis. The chromatin-linked roles are dependent on nuclear localization of Lys20, but are independent of HCS catalytic activity. Thus, Lys20 appears to have evolved as a bifunctional protein that connects cellular metabolism with chromatin functions.[Keywords: Lysine; histone; DNA damage; yeast; Htz1; bifunctional protein] Supplemental material is available at http://www.genesdev.org.

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Section: Resultsmentioning

confidence: 99%

Homocitrate synthase connects amino acid metabolism to chromatin functions through Esa1 and DNA damage

Scott¹,

Pillus²

2010

Genes Dev.

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“…Replication fork inhibition can also be obtained by the depletion of dNTPs, which can be achieved through the supply of HU (Wang and Liu, 2006;Saban and Bujak, 2009). Intriguingly, rtel1 mutants were tolerant to HU, as observed by a decreased reduction in root growth, compared with control plants ( Figure 6C).…”

Section: Rtel1 Suppresses Hrmentioning

confidence: 99%

Deficiency of the Arabidopsis Helicase RTEL1 Triggers a SOG1-Dependent Replication Checkpoint in Response to DNA Cross-Links

Cools

Kalhorzadeh

et al. 2015

The Plant Cell

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To maintain genome integrity, DNA replication is executed and regulated by a complex molecular network of numerous proteins, including helicases and cell cycle checkpoint regulators. Through a systematic screening for putative replication mutants, we identified an Arabidopsis thaliana homolog of human Regulator of Telomere Length 1 (RTEL1), which functions in DNA replication, DNA repair, and recombination. RTEL1 deficiency retards plant growth, a phenotype including a prolonged S-phase duration and decreased cell proliferation. Genetic analysis revealed that rtel1 mutant plants show activated cell cycle checkpoints, specific sensitivity to DNA cross-linking agents, and increased homologous recombination, but a lack of progressive shortening of telomeres, indicating that RTEL1 functions have only been partially conserved between mammals and plants. Surprisingly, RTEL1 deficiency induces tolerance to the deoxynucleotide-depleting drug hydroxyurea, which could be mimicked by DNA cross-linking agents. This resistance does not rely on the essential replication checkpoint regulator WEE1 but could be blocked by a mutation in the SOG1 transcription factor. Taken together, our data indicate that RTEL1 is required for DNA replication and that its deficiency activates a SOG1-dependent replication checkpoint.

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“…Hydroxyurea is a widely used antimetabolite anticancer drug. It reduces the synthesis of deoxyribonucleotides through the inhibition of ribonuclease reductase 15 . Hydroxyurea can be used safely to treat patients with ET.…”

Section: Discussionmentioning

confidence: 99%

Poststreptococcal Glomerulonephritis in a Patient with Essential Thrombocytosis

et al. 2015

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In addition to being the main cause of glomerulonephritis in children, poststreptococcal glomerulonephritis (PSGN) has recently been shown in older patients, especially those with malignancy or diabetes mellitus. The pathogenesis of PSGN has been ascribed to activation of complement 3 (C3) of the alternative complement cascade which, along with immunoglobulin (Ig) G and IgM deposits, is observed in renal tissue. Our aim here is to discuss the probable causes of PSGN developing with isolated IgM deposition in a 52-year-old patient with essential thrombocytosis followed-up over the previous 3.5 years. These characteristics make our case the first to be reported in the literature. (J Nippon Med Sch 2015; 82: 59 63)

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Hydroxyurea and hydroxamic acid derivatives as antitumor drugs

Cited by 110 publications

References 82 publications

Homocitrate synthase connects amino acid metabolism to chromatin functions through Esa1 and DNA damage

Homocitrate synthase connects amino acid metabolism to chromatin functions through Esa1 and DNA damage

Deficiency of the Arabidopsis Helicase RTEL1 Triggers a SOG1-Dependent Replication Checkpoint in Response to DNA Cross-Links

Poststreptococcal Glomerulonephritis in a Patient with Essential Thrombocytosis

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