Linked Life Data

20972458

Source:http://linkedlifedata.com/resource/pubmed/id/20972458

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2011-3-3
pubmed:abstractText
A critical observation in sporadic cancers is that not all individuals are equally prone to developing cancer following exposure to a given environmental carcinogen. Epidemiological studies have suggested that the difference in the timing of cancer onset in response to exogenous DNA damage is likely attributable to genetic variations, such as those associated with base excision repair (BER) genes. To test this long-standing hypothesis and elucidate how a genetic variation in the BER gene flap endonuclease 1 (FEN1) results in susceptibility to environment insults and causes cancer, we established a mutant mouse model carrying a point mutation (E160D) in Fen1. We demonstrate that the E160D mutation impairs the ability of FEN1 to process DNA intermediate structures in long-patch BER using nuclear extracts or reconstituted purified BER proteins. E160D cells were more sensitive to the base-damaging agents methylnitrosourea and hydrogen peroxide, leading to DNA strand breaks, chromosomal breakage and chromosome instabilities in response these DNA insults. We further show that E160D mice are significantly more susceptible to exposure to methylnitrosourea and develop lung adenocarcinoma. Thus, our current study demonstrates that a subtle genetic variation (E160D) in BER genes (FEN1) may cause a functional deficiency in repairing base damage, such that individuals carrying the mutation or similar mutations are predisposed to chemical-induced cancer development.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1476-5594
pubmed:author
pubmed:issnType
Electronic
pubmed:day
3
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1072-81
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice.
pubmed:affiliation
Key Laboratory of Chinese Ministry of Agriculture for Nuclear-Agricultural Sciences, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural