Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 731, Issue 1-2, Pages 85-91Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2011.11.009
Keywords
Flap endonuclease 1 (FEN1); Benzo[alpha]pyrene (B[alpha]P); Lung cancer; Double-stranded breaks (DSBs); Near-tetraploid aneuploidy
Funding
- NIH [R01 CA073764]
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Flap endonuclease 1 (FEN1), a member of the Rad2 nuclease family, possesses 5' flap endonuclease (FEN), 5' exonuclease (EXO), and gap-endonuclease (GEN) activities. The multiple, structure-specific nuclease activities of FEN1 allow it to process different intermediate DNA structures during DNA replication and repair. We previously identified a group of FEN1 mutations and single nucleotide polymorphisms that impair FEN1's EXO and GEN activities in human cancer patients. We also established a mouse model carrying the E160D FEN1 mutation, which mimics the mutations seen in humans. FEN1 mutant mice developed spontaneous lung cancer at high frequency at their late life stages. An important unanswered question is whether individuals carrying such FEN1 mutation are more susceptible to tobacco smoke and have an earlier onset of lung cancer. Here, we report our study on E160D mutant mice exposed to benzo[a]pyrene (B[alpha]P), a major DNA damaging compound found in tobacco smoke. We demonstrate that FEN1 employs its GEN activity to cleave DNA bubble substrates with BP-induced lesions, but the E160D FEN1 mutation abolishes such activity. As a consequence, Mouse cells carrying the E160D mutation display defects in the repair of B[alpha]P adducts and accumulate DNA double-stranded breaks and chromosomal aberrations upon treatments with B[alpha]P. Furthermore, more E160D mice than wr mice have an early onset of B[alpha]P-induced lung adenocarcinoma. All together, our current study suggests that individuals carrying the GEN-deficient FEN1 mutations have high risk to develop lung cancer upon exposure to B[alpha]P-containing agents such as tobacco smoke. (C) 2011 Elsevier B.V. All rights reserved.
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