Mechanisms underlying aflatoxin-associated mutagenesis – Implications in carcinogenesis

Research output: Contribution to journalReview article

3 Citations (Scopus)

Abstract

Chronic dietary exposure to aflatoxin B 1 (AFB 1 ), concomitant with hepatitis B infection is associated with a significant increased risk for hepatocellular carcinomas (HCCs) in people living in Southeast Asia and sub-Saharan Africa. Human exposures to AFB 1 occur through the consumption of foods that are contaminated with pervasive molds, including Aspergillus flavus. Even though dietary exposures to aflatoxins constitute the second largest global environmental risk factor for cancer development, there are still significant questions concerning the molecular mechanisms driving carcinogenesis and what factors may modulate an individual's risk for HCC. The objective of this review is to summarize key discoveries that established the association of chronic inflammation (most commonly associated with hepatitis B viral (HBV) infection) and environmental exposures to aflatoxin with increased HCC risk. Special emphasis will be given to recent investigations that have: 1) refined the aflatoxin-associated mutagenic signature, 2) expanded the DNA repair mechanisms that limit mutagenesis via adduct removal prior to replication-induced mutagenesis, 3) implicated a specific DNA polymerase in the error-prone bypass and resulting mutagenesis, and 4) identified human polymorphic variants that may modulate individual susceptibility to aflatoxin-induced cancers. Collectively, these investigations revealed that specific sequence contexts are differentially resistant against, or prone to, aflatoxin-induced mutagenesis and that these associations are remarkably similar between in vitro and in vivo analyses. These recent investigations also established DNA polymerase ζ as the major polymerase that confers the G to T transversion signature. Additionally, although the nucleotide excision repair (NER) pathway has been previously shown to repair aflatoxin-induced DNA adducts, recent murine data demonstrated that NEIL1-initiated base excision repair was significantly more important than NER relative to the removal of the highly mutagenic AFB 1 -Fapy-dG adducts. These data suggest that inactivating polymorphic variants of NEIL1 could be a potential driver of HCCs in aflatoxin-exposed populations.

Original languageEnglish (US)
Pages (from-to)76-86
Number of pages11
JournalDNA Repair
Volume77
DOIs
StatePublished - May 1 2019

Fingerprint

Mutagenesis
Aflatoxins
Carcinogenesis
Repair
DNA Repair
Aflatoxin B1
Hepatocellular Carcinoma
DNA-Directed DNA Polymerase
Hepatitis B
Nucleotides
Aspergillus flavus
Southeastern Asia
DNA Adducts
Africa South of the Sahara
Aspergillus
Environmental Exposure
Molds
Virus Diseases
Neoplasms
Fungi

Keywords

  • DNA repair
  • DNA replication
  • Hepatocellular carcinoma
  • NEIL1
  • Polymerase zeta

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Mechanisms underlying aflatoxin-associated mutagenesis – Implications in carcinogenesis. / McCullough, Amanda; Lloyd, Robert (Stephen).

In: DNA Repair, Vol. 77, 01.05.2019, p. 76-86.

Research output: Contribution to journalReview article

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abstract = "Chronic dietary exposure to aflatoxin B 1 (AFB 1 ), concomitant with hepatitis B infection is associated with a significant increased risk for hepatocellular carcinomas (HCCs) in people living in Southeast Asia and sub-Saharan Africa. Human exposures to AFB 1 occur through the consumption of foods that are contaminated with pervasive molds, including Aspergillus flavus. Even though dietary exposures to aflatoxins constitute the second largest global environmental risk factor for cancer development, there are still significant questions concerning the molecular mechanisms driving carcinogenesis and what factors may modulate an individual's risk for HCC. The objective of this review is to summarize key discoveries that established the association of chronic inflammation (most commonly associated with hepatitis B viral (HBV) infection) and environmental exposures to aflatoxin with increased HCC risk. Special emphasis will be given to recent investigations that have: 1) refined the aflatoxin-associated mutagenic signature, 2) expanded the DNA repair mechanisms that limit mutagenesis via adduct removal prior to replication-induced mutagenesis, 3) implicated a specific DNA polymerase in the error-prone bypass and resulting mutagenesis, and 4) identified human polymorphic variants that may modulate individual susceptibility to aflatoxin-induced cancers. Collectively, these investigations revealed that specific sequence contexts are differentially resistant against, or prone to, aflatoxin-induced mutagenesis and that these associations are remarkably similar between in vitro and in vivo analyses. These recent investigations also established DNA polymerase ζ as the major polymerase that confers the G to T transversion signature. Additionally, although the nucleotide excision repair (NER) pathway has been previously shown to repair aflatoxin-induced DNA adducts, recent murine data demonstrated that NEIL1-initiated base excision repair was significantly more important than NER relative to the removal of the highly mutagenic AFB 1 -Fapy-dG adducts. These data suggest that inactivating polymorphic variants of NEIL1 could be a potential driver of HCCs in aflatoxin-exposed populations.",
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