ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage

Jordan, Jennifer; Chhim, Sophea; Margulies, Carrie M; Allocca, Mariacarmela; Bronson, Roderick T.; Klungland, Arne; Samson, Leona D.; Fu, Dragony

doi:10.1038/cddis.2017.343

Cited by 14 publications

(14 citation statements)

References 73 publications

(97 reference statements)

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“…4A/B, male Alkbh7 -/hearts exhibited significantly improved post-ischemic functional recovery and significantly lower infarct size (an indicator of necrosis) compared to WT. Consistent with sexual dimorphism in the necrosis effects of ALKBH7, 16 no protection against IR injury was observed in hearts from female Alkbh7 -/mice ( Fig. S5).…”

Section: Loss Of Alkbh7 Protects the Heart From Ischemia-reperfusion supporting

confidence: 66%

“…Alkbh7 -/mice on a C57BL/6J background 16,17 were bred conventionally (WT x KO), PCR genotyped at weaning, and maintained according to the "NIH Guide" (8 th edition, 2011) on an IACUC approved protocol. Since murine Alkbh7 -/phenotypes are only seen in males, primarily male mice were used (except where indicated), with littermate wild-type controls, at of 8-12 weeks (young) or 1.5 years (old).…”

Section: Animals and Materialsmentioning

confidence: 99%

“…15 Moreover, Alkbh7 -/mice exhibit protection against alkylationinduced cell death in certain tissues. 16 Notably this phenotype is only observed in males, even though Alkbh7 is not a sex-linked gene. Furthermore, the Alkbh7 -/mouse exhibits obesity due to defective fatty acid β-oxidation, 17 and an Alkbh7 mis-sense mutation (R191Q) has been linked to prostate cancer.…”

Section: Introductionmentioning

confidence: 95%

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ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Kulkarni

Nadtochiy

Kennedy³

et al. 2020

Preprint

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Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for necrotic cell death in response to DNA alkylating agents, but its physiologic role within tissues remains unclear.Herein, we show that ALKBH7 plays a key role in the regulation of dialdehyde metabolism, which impacts cardiac survival in response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we do not find evidence that ALKBH7 functions as a prolyl-hydroxylase. However, we do find that mice lacking ALKBH7 exhibit a significant increase in glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Consistent with increased dialdehyde production, metabolomics analysis reveals rewiring of metabolic pathways related to the toxic glycolytic by-product methylglyoxal (MGO), as well as accelerated glycolysis and elevated levels of MGO protein adducts, in mice lacking ALKBH7. Consistent with roles for both necrosis and glycative stress in cardiac IR injury, hearts from male but not female Alkbh7 -/mice are protected against IR, although somewhat unexpectedly this protection does not appear to involve modulation of the mitochondrial permeability transition pore. Highlighting the importance of MGO metabolism for the observed protection, removal of glucose as a metabolic substrate or pharmacologic inhibition of GLO-1 both abrogate cardioprotection in ALKBH7 deficient mice. Integrating these observations, we propose that ALKBH7 plays a role in the regulation of glyoxal metabolism, and that protection against necrosis and IR injury bought on by ALKBH7 deficiency originates from hormetic signaling in response to elevated MGO stress.

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Section: Loss Of Alkbh7 Protects the Heart From Ischemia-reperfusion supporting

confidence: 66%

Section: Animals and Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Kulkarni

Nadtochiy

Kennedy³

et al. 2020

Preprint

Self Cite

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show abstract

“…Consistent with sexual dimorphism in the necrosis effects of ALKBH7, 16 no protection against IR injury was observed in hearts from female Alkbh7 -/mice ( Fig. 4…”

Section: Loss Of Alkbh7 Protects the Heart From Ischemia-reperfusion supporting

confidence: 60%

“…15 Moreover, Alkbh7 -/mice exhibit protection against alkylation-induced cell death in certain tissues. 16 Notably this phenotype is only observed in males, even though Alkbh7 is not a sex-linked gene. Furthermore, the Alkbh7 -/mouse exhibits obesity due to defective fatty acid β-oxidation, 17 and an Alkbh7 mis-sense mutation (R191Q) has been linked to prostate cancer.…”

Section: Introductionmentioning

confidence: 95%

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Kulkarni

Nadtochiy

Kennedy

et al. 2020

eLife

Self Cite

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Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation induced necrosis, but its function and substrates remain unclear. Herein we show ALKBH7 regulates dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find Alkbh7-/- mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in Alkbh7-/- mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from Alkbh7-/- mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.

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Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer

Sylvester

Chen

Grima

et al. 2021

Genes Chromosomes & Cancer

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Identification of cancer‐predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty‐two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β‐catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.

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ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage

Cited by 14 publications

References 73 publications

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer

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