Folate Deficiency Induces Genomic Uracil Misincorporation and Hypomethylation But Does Not Increase DNA Point Mutations

Abstract

Background and Aims-Epidemiologic studies have linked nutritional folate deficiency to an increased risk of cancer, but recent trials suggest that folate supplementation does not protect against tumor formation. Our aim was to analyze the genetic and epigenetic consequences of folate deficiency and to investigate whether impairment of the uracil base excision repair pathway can enhance its effects.

CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

“…Folate is an essential cofactor for one-carbon methyl transfer reactions and crucial for a variety of biological processes, such as synthesis and repair of DNA (Blount et al 1997;Kronenberg et al 2008;Linhart et al 2008), regulation of gene expression (Ghoshal et al 2006;Pogribny et al 2008), and synthesis of amino acids and neurotransmitters (Fournier et al 2002;Shinohara et al 2006). Since the 1940s, folate-deficient states and inborn errors of folate metabolism including defective transport have increasingly been recognized to play a role in the development of a macrocytic anemia, atherosclerosis, thrombosis, neuropsychiatric disorders, and neural tube defects (Surtees et al 1993).…”

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…On the other hand, the data on the effects of folate and Ung deficiency on point mutations showed that folate deficiency had no significant effect on the frequency or spectrum of point mutations on wild-type or Ung -/-mice. In particular, the study failed to detect an increase in point mutations at T:A base pairs, resulting from repair of uracil misincorporation (Linhart et al, 2009). The authors concluded that although folate deficiency causes an increase in genomic uracil content through uracil misincorporation, it does not lead to an increase in DNA point mutations; nor does it increase transition mutations at CpG sites.…”

“…The resultant U:A base pairs are potentially mutagenic because of secondary repair activity that can generate abasic sites (Auerbach et al, 2005), creating point mutations or chromosomal breaks at T:A base pairs (Linhart et al, 2009). Subsequently, folate deficiency is believed to dramatically decrease DNA repair efficiency as it disturbs nucleotide syntheses, promoting DNA damage, via chromosomal breakage (Sibany et al, 2002;Zhang et al, 2003).…”

“…The results in this study are in line with those obtained by Linhart and co-authors on wild-type mice that were placed on a folate deficient diet for a duration of 8 months. The authors found that folate deficiency induced genomic uracil misincorporation and hypomethylation but did not increase DNA point mutations, indicating that the effects of a low-folate diet on DNA methylation and point mutations are insufficient to promote tumor development (Linhart et al, 2009). Moreover, Van Guelpen and co-authors reported that folate deficiency can decrease the risk of intestinal tumor (Van Guelpen et al, 2006), and according to some recent epidemiological studies, folate supplementation either had no effect (Logan et al, 2008) or increased the risk of intestinal tumors (Cole et al, 2007).…”

“…The in vivo study conducted by Linhart and co-authors, mentioned above, aimed to establish whether chronic folate deficiency alone or with additional mutations in the DNA repair pathway may affect the frequency and spectra of mutations in non-tumor tissues. The genetic effects of folate deficiency were examined after a subjection of 3-month-old wild type and uracil DNA glycosylase (Ung) knockout mice (Ung -/-) to an 8-month folate-deficient diet (Linhart et al, 2009). Ung is an excision repair enzyme that removes misincorporated uracil during DNA replication (Nilsen et al, 2000) and repairs U:G mispairs that occur as a result of cytosine deamination .…”