ALDH9A1 Deficiency as a Source of Endogenous DNA Damage that Requires Repair by the Fanconi Anemia Pathway

Jung, Moonjung; Ilyashov, Isaac; Park, Yeji; Donovan, Frank X.; Bhojappa, Raman Ramanagoudr; Keahi, Danielle; Durmaz, Jordan A.; Choijilsuren, Haruna B; Goldfarb, Audrey; Stein, Mia; Kim, Jung-Woo; White, Ryan R.; Sridhar, Sunandini; Noonan, Raymond J.; Wiley, Tom; Carroll, Thomas; Lach, Francis P.; Auerbach, Arleen D.; Miranda, Ileana C.; Chandrasekharappa, Settara C.; Smogorzewska, Agata

doi:10.1101/2022.05.26.493623

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…1) oxidizes a broad range of aldehyde substrates to the corresponding acids such as γ -aminobutyraldehyde to γ -aminobutyric acid (Kaisaki et al, 2014). Its deficiency causes DNA damage leading to genomic instability and potential tumorigenesis (Jung et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

A new view on functions of the lysine demalonylase activity of SIRT5

Nahálková¹

2022

Preprint

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The substrate specificity of the pharmaceutically attractive tumor-promoter SIRT5 was already investigated multiple times by advanced proteomic tools. However, the present pathway enrichment and gene function prediction analysis bring new highlights to the overall knowledge about the lysine demalonylation activity of SIRT5, a member of the sirtuin family with many roles in aging and age-related diseases. It shows previously unreported aspects of the involvement of the lysine demalonylated SIRT5 substrates in Eukaryotic translation elongation (ETE), Amino acid and derivative metabolism (AADM), and Selenoamino acid metabolism (SAM). The cluster of the elongation factors (EEF1A1, EEF2, EEF1D, and EEF1G) belonging to ETE participates in the peptide chain elongation and the export of the tRNA-s from the nucleus the primary sites of the proteosynthesis. SIRT5 regulates key enzymes with tumor-promoting functions involved in AADM (GLUD1, SHMT1, ACAT1), which fits its experimentally proven tumor promoter functions. In contrast, SIRT5 also lysine demalonylates tumor suppressor substrates involved in AADM and SAM (ALDH9A1, BHMT, GNMT). It indicates comparable functions like directly interacting family member SIRT3, which was reported to have dual tumor promoter/oncogene functions. Similar to the roles of the sirtuins, the SAM pathway impacts longevity, protects against cardiovascular diseases, and is associated with hepatic steatosis. The selen supplementation also mediates the calorie restriction effect, which increases the NAD+/NADH ratio in the cells and stimulates the expression of SIRT5 and other sirtuins. SIRT5 in turn regulates the selenocysteine synthesis through the lysine demalonylation of the participating ribosomal proteins, SECISBP2 and GNMT, which creates a regulatory loop.

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Section: Resultsmentioning

confidence: 99%

A new view on functions of the lysine demalonylase activity of SIRT5

Nahálková¹

2022

Preprint

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“…Prior studies suggest that different tissues and cells may display vulnerability to different endogenous sources of genome instability (Langevin et al 2011;Garaycoechea et al 2012;Dingler et al 2020;Jung et al 2022). It is unclear why the GCPs would be particularly vulnerable to instability at G4s.…”

Section: Discussionmentioning

confidence: 99%

G-quadruplexes are a source of vulnerability inBRCA2deficient granule cell progenitors and medulloblastoma

Keahi,

Sanders,

Paul

et al. 2024

Preprint

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Biallelic pathogenic variants in the essential DNA repair geneBRCA2causes Fanconi anemia, complementation group FA-D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under SHH activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four ofBrca2in the central nervous system, coupled with globalTrp53loss.Brca2Δex3-4;Trp53-/-animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping G-quadruplexes (G4s).Brca2-deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin.Pif1helicase, which resolves G4s during replication, was highly upregulated in tumors, andPif1knockout in primary MB tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment ofBRCA2-deficient medulloblastomas.

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“…1) oxidizes a broad range of aldehyde substrates to the corresponding acids such as γaminobutyraldehyde to γ-aminobutyric acid [39]. Its deficiency causes DNA damage leading to genomic instability and potential tumorigenesis [40].…”

Section: Amino Acid and Derivative Metabolism (Aadm)mentioning

confidence: 99%

A new view on functions of the lysine demalonylase activity of SIRT5

Nahálková

2023

Life Sciences

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ALDH9A1 Deficiency as a Source of Endogenous DNA Damage that Requires Repair by the Fanconi Anemia Pathway

Cited by 4 publications

References 39 publications

A new view on functions of the lysine demalonylase activity of SIRT5

A new view on functions of the lysine demalonylase activity of SIRT5

G-quadruplexes are a source of vulnerability inBRCA2deficient granule cell progenitors and medulloblastoma

A new view on functions of the lysine demalonylase activity of SIRT5

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