Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms

Wu, Ying; Mensink, Rgj; Verlind, E; Sijmons, Rolf H.; Buys, Charles H.C.M.; Hofstra, Robert M.W.; Berends, Maran J.W.; Kleibeuker, Jan H.; Post, Jan G.; Kempinga, Claudia; Sluis, Tineke van der; Hollema, Harry; Zee, Ate G.J. van der

doi:10.1053/gast.2001.25117

Cited by 123 publications

(92 citation statements)

References 16 publications

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“…48 Based on the mutator phenotype of yeast Exo I mutants, EXOI/HEXI is likely to play a role in MMR. This is confirmed by the detection of germline mutations of the EXO1 gene 49 in patients affected with hereditary colorectal cancer, the disease linked to MMR gene mutations (see below).…”

Section: Additional Interactions In Mmr During Excision and Resynthesismentioning

confidence: 73%

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

2001

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The mismatch repair (MMR) system promotes genomic fidelity by repairing base-base mismatches, insertion-deletion loops and heterologies generated during DNA replication and recombination. This function is critically dependent on the assembling of multimeric complexes involved in mismatch recognition and signal transduction to downstream repair events. In addition, MMR proteins coordinate a complex network of physical and functional interactions that mediate other DNA transactions, such as transcription-coupled repair, base excision repair and recombination. MMR proteins are also involved in activation of cell cycle checkpoint and induction of apoptosis when DNA damage overwhelms a critical threshold. For this reason, they play a role in cell death by alkylating agents and other chemotherapeutic drugs, including cisplatin. Inactivation of MMR genes in hereditary and sporadic cancer is associated with a mutator phenotype and inhibition of apoptosis. In the future, a deeper understanding of the molecular mechanisms and functional interactions of MMR proteins will lead to the development of more effective cancer prevention and treatment strategies.

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Section: Additional Interactions In Mmr During Excision and Resynthesismentioning

confidence: 73%

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

2001

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“…Eukaryotic EXO1 is a member of the Rad2/FEN1 family of nucleases (Lee and Wilson 1999) (Table 2) and is one of four nucleases that may be involved in MMR, although it is not (as originally reported) an orthologue of the Escherichia coli MMR protein EXO1 (Genschel et al 2002;Tishkoff et al 1997Tishkoff et al , 1998. There are some reports that loss of EXO1 gives rise to one form of the MMR-deficient syndrome human nonpolyposis colon cancer, HNPCC (Wu et al 2001), but a direct association has been questioned (Thompson et al 2004). Eukaryotic EXO1 is involved in various DNA metabolic pathways other than MMR, including meiosis (Fiorentini et al 1997) and recombination (Tsubouchi and Ogawa 2000).…”

Section: Replication Fidelity Is Enhanced Through Nucleases Acting Inmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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“…Several groups have examined the role of EXO1 in colon cancer predisposition. Wu et al (2001) identified EXO1 mutations in HNPCC families reporting loss of heterozygosity (LOH) of the mutant allele in tumors; and EXO1 was proposed to be a high or moderate penetrance colorectal cancer (CRC) predisposition gene (Wu et al, 2001). These data were unusual because the tumor cells reportedly had lost the mutated allele rather than the wild-type (WT) allele.…”

Section: Introductionmentioning

confidence: 99%

“…The investigators argued that complete loss of EXO1 might be lethal, but this suggestion was at odds with viability of Exo1 null yeast and the Exo1 mutant mice (Wei et al, 2003;Tran et al, 2004). Because the variants that were reported by Wu et al (2001) were subsequently found to be common variants in normal populations, several investigators concluded that EXO1 probably does not play a major causative role in classical HNPCC (Alam et al, 2003;Jagmohan-Changur et al, 2003). However, recently two EXO1 single nucleotide polymorphisms (SNPs) have been shown to have a significant association with the development of CRC (Yamamoto et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Tumor progression in Apc1638N mice with Exo1 and Fen1 deficiencies

et al. 2007

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Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms

Cited by 123 publications

References 16 publications

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Tumor progression in Apc1638N mice with Exo1 and Fen1 deficiencies

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