ALDH9A1 deficiency as a source of endogenous DNA damage that requires repair by the Fanconi anemia pathway

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Fanconi anemia (FA) is a rare genetic disorder characterized by DNA repair defects, leading to bone marrow failure and cancer.
• The FA pathway is essential for repairing DNA interstrand cross-links (ICLs), which can arise from endogenous metabolites.
• Previous research implicated acetaldehyde and formaldehyde in FA pathogenesis, but other toxic metabolites remain understudied.

Purpose of the Study:

• To investigate the role of other toxic metabolites in Fanconi anemia (FA) pathogenesis.
• To identify novel synthetic lethal interactions with FA pathway deficiencies.
• To explore potential therapeutic strategies for FA by targeting metabolic pathways.

Main Methods:

• A metabolism-focused CRISPR screen was employed to identify genes synthetically lethal with FA pathway deficiency.
• CRISPR screens were used to assess the impact of ALDH9A1 deficiency and polyamine transporter ATP13A3 on cellular viability and genomic stability.
• Hematopoietic stem cell (HSC) function and tumor development were evaluated in Fanca-/-Aldh9a1-/- mice.

Main Results:

• A synthetically lethal interaction was discovered between ALDH9A1 deficiency and FA pathway defects.
• Combined deficiency of ALDH9A1 and FANCD2 resulted in genomic instability, apoptosis, and impaired hematopoietic colony formation.
• Fanca-/-Aldh9a1-/- mice showed an increased incidence of ovarian tumors, and loss of ATP13A3 improved survival in double-deficient cells.

Conclusions:

• ALDH9A1 deficiency exacerbates FA pathogenesis by increasing DNA damage.
• High intracellular polyamines and their metabolites (3-aminopropanal, acrolein) are identified as endogenous sources of DNA damage in FA patients.
• Targeting polyamine metabolism or related pathways may offer novel therapeutic avenues for Fanconi anemia.