Hereditary nonpolyposis colorectal cancer (lynch syndromes I and II). I. Clinical description of resource

Lynch, Henry T.; Kimberling, William J.; Albano, William A.; Lynch, Jane F.; Biscone, Karen A.; Schuelke, Guy S.; Sandberg, Avery A.; Lipkin, Martin; Deschner, Eleanor E.; Mikol, Yves B.; Elston, Robert C.; Bailey-Wilson, Joan E.; Danes, B. Shannon

doi:10.1002/1097-0142(19850815)56:4<934::aid-cncr2820560439>3.0.co;2-i

Cited by 269 publications

(58 citation statements)

References 13 publications

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“…Early reactions of MMR are performed by MutS and MutL proteins, which are widely conserved in species from bacteria to human (3,4). It is known that in human, mutations and epigenetic silencing of genes encoding MutS and MutL homologues cause Lynch syndrome, which is characterized by early-onset colorectal and other cancers (5)(6)(7)(8).…”

Section: Dna Mismatch Repair (Mmr)mentioning

confidence: 99%

Structural Features and Functional Dependency on β-Clamp Define Distinct Subfamilies of Bacterial Mismatch Repair Endonuclease MutL

Fukui

Baba

Kumasaka

et al. 2016

Journal of Biological Chemistry

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In early reactions of DNA mismatch repair, MutS recognizes mismatched bases and activates MutL endonuclease to incise the error-containing strand of the duplex. DNA sliding clamp is responsible for directing the MutL-dependent nicking to the newly synthesized/error-containing strand. In Bacillus subtilis MutL, the ␤-clamp-interacting motif (␤ motif) of the C-terminal domain (CTD) is essential for both in vitro direct interaction with ␤-clamp and in vivo repair activity. A large cluster of negatively charged residues on the B. subtilis MutL CTD prevents nonspecific DNA binding until ␤ clamp interaction neutralizes the negative charge. We found that there are some bacterial phyla whose MutL endonucleases lack the ␤ motif. For example, the region corresponding to the ␤ motif is completely missing in Aquifex aeolicus MutL, and critical amino acid residues in the ␤ motif are not conserved in Thermus thermophilus MutL. We then revealed the 1.35 Å-resolution crystal structure of A. aeolicus MutL CTD, which lacks the ␤ motif but retains the metalbinding site for the endonuclease activity. Importantly, there was no negatively charged cluster on its surface. It was confirmed that CTDs of ␤ motif-lacking MutLs, A. aeolicus MutL and T. thermophilus MutL, efficiently incise DNA even in the absence of ␤-clamp and that ␤-clamp shows no detectable enhancing effect on their activity. In contrast, CTD of Streptococcus mutans, a ␤ motif-containing MutL, required ␤-clamp for the digestion of DNA. We propose that MutL endonucleases are divided into three subfamilies on the basis of their structural features and dependence on ␤-clamp.

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Section: Dna Mismatch Repair (Mmr)mentioning

confidence: 99%

Structural Features and Functional Dependency on β-Clamp Define Distinct Subfamilies of Bacterial Mismatch Repair Endonuclease MutL

Fukui

Baba

Kumasaka

et al. 2016

Journal of Biological Chemistry

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“…It is also pertinent to note that Lynch et al 54,55 had previously classified families into Lynch syndrome I, which was characterized by families with increased CRC risk but lacking associated extracolonic cancers, and Lynch syndrome II, which contained the associated integral cancers in addition to CRC excess. These studies took place in the 1980s, prior to knowledge about MMR mutations and their causal significance in the Lynch syndrome.…”

Section: Amsterdam Criteria Positive But Mmr-negative Cohortmentioning

confidence: 99%

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

et al. 2006

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“…Entre estas características, a presença de tumores sincrônicos nestes pacientes com HNPCC é achado muito mais freqüente quando comparado aos pacientes com tumor esporádico 8,11,14 .…”

Section: Abcddv/518unclassified

A expressão de genes reparadores do DNA nos tumores sincrônicos de câncer colorretal esporádico

Proscurshim

Perez

Santos

et al. 2007

ABCD, arq. bras. cir. dig.

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InTRODUÇÃOO câncer colorretal (CCR) persiste como uma das neoplasias mais freqüentes no mundo ocidental, estimando-se aproximadamente 150 mil casos novos nos Estados Unidos e cerca de 20 mil no Brasil 7,15 .A descoberta de mecanismos genéticos e moleculares envolvidos no processo da carcinogênese colorretal permitiu a identificação de uma síndrome hereditária com grande suscetibilidade para algumas neoplasias (além do CCR) conhecida como síndrome hereditária não-polipóide do câncer colorretal (HNPCC -Hereditary Non-Polyposis Colorectal Cancer). Atualmente, acredita-se que estes pacientes possam corresponder a cerca de 10% dos casos de neoplasia colorretal.Nesta síndrome hereditária, acredita-se que o mecanismo genético envolvido no processo de carcinogênese inclui defeitos no mecanismo de reparo do DNA, levando à ocorrência de erros freqüentes de replicação -fenômeno conhecido como instabilidade de microssatélites -. Com isso, foram identificadas alterações nos genes de proteí-nas envolvidas no processo de reparo do DNA, sendo os genes mais frequentemente afetados o MSH2, MLH1 e MSH6 0 .Ao contrário, tumores ditos esporádicos, estariam associados a mutação e ativação de proto-oncogenes (mais frequentemente o K-ras) assim como a deleção de áreas cromossômicas de genes supressores de tumor (como p53, DCC e APC) 5 . ABCDDV/518Além de estar associada a mecanismos genéticos e moleculares distintos das neoplasias colorretais usuais, pacientes com HNPCC apresentam características clinicas, patológicas e prognóstico que também os diferenciam dos pacientes com neoplasia esporádica. Entre estas características, a presença de tumores sincrônicos nestes pacientes com HNPCC é achado muito mais freqüente quando comparado aos pacientes com tumor esporádico 8,11,14 .Apesar disso, uma parcela significativa (até 15%) dos pacientes com tumor esporádico pode apresentar alterações genéticas compatíveis com defeito no mecanismo de reparo do DNA e instabilidade de microssatélites 8 .A ocorrência deste fenômeno poderia justificar a presença nestes pacientes com tumor esporádico de características clinicas e patológicas semelhantes aos tumores de pacientes com HNPCC.Por esta razão decidiu-se, por objetivo deste trabalho, investigar as alterações dos genes responsáveis pelo mecanismo de reparo do DNA em pacientes com tumor esporádico e manifestação clínica muito característica dos tumores HNPCC, a presença de tumores sincrônicos. MÉTODOSPacientes com adenocarcinoma do cólon ou do reto tratados pela Disciplina de Coloproctologia da Faculdade

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Hereditary nonpolyposis colorectal cancer (lynch syndromes I and II). I. Clinical description of resource

Cited by 269 publications

References 13 publications

Structural Features and Functional Dependency on β-Clamp Define Distinct Subfamilies of Bacterial Mismatch Repair Endonuclease MutL

Structural Features and Functional Dependency on β-Clamp Define Distinct Subfamilies of Bacterial Mismatch Repair Endonuclease MutL

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

A expressão de genes reparadores do DNA nos tumores sincrônicos de câncer colorretal esporádico

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