Complexos de reparo mismatch: mecanismos e funções
Palavras-chave:
Reparo de DNA Mismatch. MutL. MutS. MSH2.Resumo
As proteínas do Reparo de DNA Mismatch (MMR) são encontradas em diversos mecanismos importantes de funções celulares. A principal função dessas proteínas está relacionada ao reparo pós replicacional do
DNA, corrigindo as bases incorporadas incorretamente ao genoma devido ao erro de replicação. A perda das
funções das proteínas MMR é geralmente aumentada devido a mutações espontâneas em organismos, que vão
desde bactérias a humanos. As mutações nos genes MMR causam câncer colorretal hereditário não-poliposo,
e, a perda das funções dos genes MMR está associada com uma significativa fração de cânceres esporádicos.
Esta revisão busca resumir os principais mecanismos moleculares das funções protéicas dos MMR. O conhecimento acerca do mecanismo de reparo MMR está em processo de crescimento ao longo dos anos, embora a complexidade de suas vias de sinalização, ainda, permanece pouco conhecida. O entendimento desses
mecanismos, portanto, faz-se crucial para maior suporte no desenvolvimento de novos alvos terapêuticos para
doenças relacionadas a essa via de reparo.
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Referências
BENACHENHOU, N. et al. Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1
and hMSH3 in sporadic breast cancer. Br. J. Cancer,
v. 79, n.7-8, p.1012-1017, Mar. 1999.
BROWN, K. D. et al. The mismatch repair system is
required for S-phase checkpoint activation. Nat.Genet., v. 33, n.1, p.80-84, Jan. 2003.
BUERMEYER, A. B. et al. Mammalian DNA mismatch repair. Annu. Rev Genet., v. 33, n.533-564,
1999.
CHEN, S. K. et al. Determination of 8-oxoguanine
in individual cell nucleus of gamma-irradiated mammalian cells. Radiat. Res., v. 155, n.6, p.832-836, Jun.
2001.
FINK, D. et al. The effect of different chemotherapeutic agents on the enrichment of DNA mismatch
repair-deficient tumour cells. Br. J. Cancer, v. 77, n.5,
p.703-708, Mar. 1998.
FLORES-ROZAS, H.; CLARK, D.; KOLODNER,
R. D. Proliferating cell nuclear antigen and Msh2pMsh6p interact to form an active mispair recognition complex. Nat. Genet., v. 26, n.3, p.375-378, Nov.
2000.
GENSCHEL, J.; MODRICH, P. Mechanism of 5'-directed excision in human mismatch repair. Mol. Cell,
v. 12, n. 5, p.1077-1086, Nov. 2003.
GRADY, W. M.; MARKOWITZ, S. D. Genetic and
epigenetic alterations in colon cancer. Annu.Rev
Genomics Hum.Genet., v. 3, p. 101-128, 2002.
GRIFFIN, S. et al. DNA mismatch binding and incision at modified guanine bases by extracts of mammalian cells: implications for tolerance to DNA
methylation damage. Biochemistry, v. 33, n. 16, p.
4787-4793, Apr. 1994.
HARRINGTON, J. M.; KOLODNER, R. D. Saccharomyces cerevisiae Msh2-Msh3 acts in repair of
base-base mispairs. Mol.Cell Biol., v. 27, n. 18, p.
6546-6554, Sep. 2007.
IYER, R. R. et al. DNA mismatch repair: functions
and mechanisms. Chem.Rev., v. 106, n. 2, p. 302-323,
Feb. 2006a.
IYER, R. R. et al. DNA mismatch repair: functions
and mechanisms. Chem.Rev., v. 106, n. 2, p. 302-323,
Feb. 2006b.
JIRICNY, J. The multifaceted mismatch-repair system. Nat.Rev.Mol.Cell Biol., v. 7, n. 5, p. 335-346,
May. 2006.
KADYROV, F. A. et al. Endonucleolytic function of
MutLalpha in human mismatch repair. Cell, v. 126,
n. 2, p. 297-308, Jul. 2006.
KANE, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1
in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res., v. 57, n.
5, p. 808-811, Mar. 1997.
KAT, A. et al. An alkylation-tolerant, mutator human
cell line is deficient in strand-specific mismatch repair. Proc.Natl.Acad.Sci.U.S.A, v. 90, n. 14, p. 6424-
6428, Jul. 1993.
LAHUE, R. S.; AU, K. G.; MODRICH, P. DNA mismatch correction in a defined system. Science, v. 245,
n. 4914, p.160-164, Jul. 1989.
LANZA, G. et al. Immunohistochemical pattern of
MLH1/MSH2 expression is related to clinical and
pathological features in colorectal adenocarcinomas
with microsatellite instability. Mod.Pathol., v. 15, n.
7, p.741-749, Jul. 2002.
LEACH, F. S. et al. Expression of the human mismatch repair gene hMSH2: a potential marker for
urothelial malignancy. Cancer, v. 88, n.10, p.2333-
2341, May. 2000.
LEE, S. D.; ALANI, E. Analysis of interactions between mismatch repair initiation factors and the replication processivity factor PCNA. J.Mol.Biol., v. 355,
n. 2, p.175-184, Jan. 2006.
LEUNG, S. Y. et al. hMLH1 promoter methylation
and lack of hMLH1 expression in sporadic gastric
carcinomas with high-frequency microsatellite instability. Cancer Res., v. 59, n. 1, p.159-164, Jan. 1999.
LI, G. M. Mechanisms and functions of DNA mismatch repair. Cell Res., v. 18, n.1, p.85-98, Jan. 2008.
LIN, Z.; NEI, M.; MA, H. The origins and early evolution of DNA mismatch repair genes--multiple horizontal gene transfers and co-evolution. Nucleic Acids
Res., v. 35, n.22, p.7591-7603, 2007.
MARCUS, V. A. et al. Immunohistochemistry for
hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors. Am.J.Surg.Pathol., v.
23, n.10, p.1248-1255, Oct. 1999.
MODRICH, P. Mechanisms in eukaryotic mismatch
repair. J.Biol.Chem., v. 281, n. 41, p.30305-30309, Oct.
2006.
MODRICH, P.; LAHUE, R. Mismatch repair in replication fidelity, genetic recombination, and cancer
biology. Annu.Rev.Biochem., v. 65, n.101-133, 1996.
NI, T. T.; MARSISCHKY, G. T.; KOLODNER, R. D.
MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S.
cerevisiae. Mol.Cell, v. 4, n. 3, p.439-444, Sep. 1999.
NOWOSIELSKA, A.; MARINUS, M. G. DNA mismatch repair-induced double-strand breaks. DNA
Repair (Amst), v. 7, n.1, p.48-56, Jan. 2008.
NUNN, J. et al. Allelic imbalance at the DNA mismatch repair loci, hMSH2, hMLH1, hPMS1, hPMS2
and hMSH3, in squamous cell carcinoma of the head
and neck. Oral Oncol., v. 39, n. 2, p.115-129, Feb.
2003.
O'BRIEN, V.; BROWN, R. Signalling cell cycle arrest
and cell death through the MMR System. Carcinogenesis, v. 27, n. 4, p. 682-692, Apr. 2006.
OHRLING, K. et al. Mismatch repair protein expression is an independent prognostic factor in sporadic
colorectal cancer. Acta Oncol., v. 49, n. 6, p.797-804,
Mar. 2010.
PELTOMAKI, P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J. Clin.
Oncol., v. 21, n. 6, p.1174-1179, Mar. 2003.
SARGENT, D. J. et al. Defective Mismatch Repair As
a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer. J.
Clin. Oncol., v. 28, n. 20, p. 3219-26, May. 2010.
SCHOFIELD, M. J.; HSIEH, P. DNA mismatch repair: molecular mechanisms and biological function.
Annu. Rev. Microbiol., v. 57, n. 579-608, 2003.
SELMANE, T. et al. Formation of a DNA mismatch
repair complex mediated by ATP. J. Mol. Biol., v. 334,
n. 5, p. 949-965, Dec. 2003.
STOJIC, L. et al. Mismatch repair-dependent G2
checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase. Genes Dev., v.
18, n.11, p.1331-1344, Jun. 2004.
THIBODEAU, S. N. et al. Altered expression of
hMSH2 and hMLH1 in tumors with microsatellite
instability and genetic alterations in mismatch repair
genes. Cancer Res., v. 56, n. 21, p. 4836-4840, Nov.
1996.
UEHARA, H. et al. Deficiency of hMLH1 and hMSH2
expression is a poor prognostic factor in esophageal
squamous cell carcinoma. J. Surg. Oncol., v. 92, n.2,
p.109-115, Nov. 2005.
UMAR, A. et al. Requirement for PCNA in DNA
mismatch repair at a step preceding DNA resynthesis. Cell, v. 87, n.1, p.65-73, Oct. 1996.
UMAR, A.; KUNKEL, T. A. DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur.J.Biochem., v. 238, n. 2, p. 297-307, Jun.1996.
YAN, T. et al. DNA mismatch repair (MMR) mediates 6-thioguanine genotoxicity by introducing single-strand breaks to signal a G2-M arrest in MMRproficient RKO cells. Clin.Cancer Res., v. 9, n. 6, p.
2327-2334, Jun. 2003.
YOUN, C. K. et al. Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity. Nat.Cell Biol., v. 7, n. 2, p. 137-
147, Feb. 2005.
ZEKRI, A. R. et al. Mismatch repair genes (hMLH1,
hPMS1, hPMS2, GTBP/hMSH6, hMSH2) in the
pathogenesis of hepatocellular carcinoma. World
J.Gastroenterol., v. 11, n. 20, p. 3020-3026, May. 2005.
ZENG, M. et al. Ionizing radiation-induced apoptosis via separate Pms2- and p53-dependent pathways.
Cancer Res., v. 60, n. 17, p. 4889-4893, Sep. 2000.
ZHANG, H. et al. Apoptosis induced by overexpression of hMSH2 or hMLH1. Cancer Res., v. 59, n. 13,
p. 3021-3027, Jul. 1999.
ZHANG, Y. et al. Reconstitution of 5'-directed human mismatch repair in a purified system. Cell, v.
122, n. 5, p. 693-705, Sep. 2005.
ZIENOLDDINY, S. et al. Msh2 deficiency increases
susceptibility to benzo[a]pyrene-induced lymphomagenesis. Int.J.Cancer, v. 118, n. 11, p. 2899-2902,
Jun. 2006.
and hMSH3 in sporadic breast cancer. Br. J. Cancer,
v. 79, n.7-8, p.1012-1017, Mar. 1999.
BROWN, K. D. et al. The mismatch repair system is
required for S-phase checkpoint activation. Nat.Genet., v. 33, n.1, p.80-84, Jan. 2003.
BUERMEYER, A. B. et al. Mammalian DNA mismatch repair. Annu. Rev Genet., v. 33, n.533-564,
1999.
CHEN, S. K. et al. Determination of 8-oxoguanine
in individual cell nucleus of gamma-irradiated mammalian cells. Radiat. Res., v. 155, n.6, p.832-836, Jun.
2001.
FINK, D. et al. The effect of different chemotherapeutic agents on the enrichment of DNA mismatch
repair-deficient tumour cells. Br. J. Cancer, v. 77, n.5,
p.703-708, Mar. 1998.
FLORES-ROZAS, H.; CLARK, D.; KOLODNER,
R. D. Proliferating cell nuclear antigen and Msh2pMsh6p interact to form an active mispair recognition complex. Nat. Genet., v. 26, n.3, p.375-378, Nov.
2000.
GENSCHEL, J.; MODRICH, P. Mechanism of 5'-directed excision in human mismatch repair. Mol. Cell,
v. 12, n. 5, p.1077-1086, Nov. 2003.
GRADY, W. M.; MARKOWITZ, S. D. Genetic and
epigenetic alterations in colon cancer. Annu.Rev
Genomics Hum.Genet., v. 3, p. 101-128, 2002.
GRIFFIN, S. et al. DNA mismatch binding and incision at modified guanine bases by extracts of mammalian cells: implications for tolerance to DNA
methylation damage. Biochemistry, v. 33, n. 16, p.
4787-4793, Apr. 1994.
HARRINGTON, J. M.; KOLODNER, R. D. Saccharomyces cerevisiae Msh2-Msh3 acts in repair of
base-base mispairs. Mol.Cell Biol., v. 27, n. 18, p.
6546-6554, Sep. 2007.
IYER, R. R. et al. DNA mismatch repair: functions
and mechanisms. Chem.Rev., v. 106, n. 2, p. 302-323,
Feb. 2006a.
IYER, R. R. et al. DNA mismatch repair: functions
and mechanisms. Chem.Rev., v. 106, n. 2, p. 302-323,
Feb. 2006b.
JIRICNY, J. The multifaceted mismatch-repair system. Nat.Rev.Mol.Cell Biol., v. 7, n. 5, p. 335-346,
May. 2006.
KADYROV, F. A. et al. Endonucleolytic function of
MutLalpha in human mismatch repair. Cell, v. 126,
n. 2, p. 297-308, Jul. 2006.
KANE, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1
in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res., v. 57, n.
5, p. 808-811, Mar. 1997.
KAT, A. et al. An alkylation-tolerant, mutator human
cell line is deficient in strand-specific mismatch repair. Proc.Natl.Acad.Sci.U.S.A, v. 90, n. 14, p. 6424-
6428, Jul. 1993.
LAHUE, R. S.; AU, K. G.; MODRICH, P. DNA mismatch correction in a defined system. Science, v. 245,
n. 4914, p.160-164, Jul. 1989.
LANZA, G. et al. Immunohistochemical pattern of
MLH1/MSH2 expression is related to clinical and
pathological features in colorectal adenocarcinomas
with microsatellite instability. Mod.Pathol., v. 15, n.
7, p.741-749, Jul. 2002.
LEACH, F. S. et al. Expression of the human mismatch repair gene hMSH2: a potential marker for
urothelial malignancy. Cancer, v. 88, n.10, p.2333-
2341, May. 2000.
LEE, S. D.; ALANI, E. Analysis of interactions between mismatch repair initiation factors and the replication processivity factor PCNA. J.Mol.Biol., v. 355,
n. 2, p.175-184, Jan. 2006.
LEUNG, S. Y. et al. hMLH1 promoter methylation
and lack of hMLH1 expression in sporadic gastric
carcinomas with high-frequency microsatellite instability. Cancer Res., v. 59, n. 1, p.159-164, Jan. 1999.
LI, G. M. Mechanisms and functions of DNA mismatch repair. Cell Res., v. 18, n.1, p.85-98, Jan. 2008.
LIN, Z.; NEI, M.; MA, H. The origins and early evolution of DNA mismatch repair genes--multiple horizontal gene transfers and co-evolution. Nucleic Acids
Res., v. 35, n.22, p.7591-7603, 2007.
MARCUS, V. A. et al. Immunohistochemistry for
hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors. Am.J.Surg.Pathol., v.
23, n.10, p.1248-1255, Oct. 1999.
MODRICH, P. Mechanisms in eukaryotic mismatch
repair. J.Biol.Chem., v. 281, n. 41, p.30305-30309, Oct.
2006.
MODRICH, P.; LAHUE, R. Mismatch repair in replication fidelity, genetic recombination, and cancer
biology. Annu.Rev.Biochem., v. 65, n.101-133, 1996.
NI, T. T.; MARSISCHKY, G. T.; KOLODNER, R. D.
MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S.
cerevisiae. Mol.Cell, v. 4, n. 3, p.439-444, Sep. 1999.
NOWOSIELSKA, A.; MARINUS, M. G. DNA mismatch repair-induced double-strand breaks. DNA
Repair (Amst), v. 7, n.1, p.48-56, Jan. 2008.
NUNN, J. et al. Allelic imbalance at the DNA mismatch repair loci, hMSH2, hMLH1, hPMS1, hPMS2
and hMSH3, in squamous cell carcinoma of the head
and neck. Oral Oncol., v. 39, n. 2, p.115-129, Feb.
2003.
O'BRIEN, V.; BROWN, R. Signalling cell cycle arrest
and cell death through the MMR System. Carcinogenesis, v. 27, n. 4, p. 682-692, Apr. 2006.
OHRLING, K. et al. Mismatch repair protein expression is an independent prognostic factor in sporadic
colorectal cancer. Acta Oncol., v. 49, n. 6, p.797-804,
Mar. 2010.
PELTOMAKI, P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J. Clin.
Oncol., v. 21, n. 6, p.1174-1179, Mar. 2003.
SARGENT, D. J. et al. Defective Mismatch Repair As
a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer. J.
Clin. Oncol., v. 28, n. 20, p. 3219-26, May. 2010.
SCHOFIELD, M. J.; HSIEH, P. DNA mismatch repair: molecular mechanisms and biological function.
Annu. Rev. Microbiol., v. 57, n. 579-608, 2003.
SELMANE, T. et al. Formation of a DNA mismatch
repair complex mediated by ATP. J. Mol. Biol., v. 334,
n. 5, p. 949-965, Dec. 2003.
STOJIC, L. et al. Mismatch repair-dependent G2
checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase. Genes Dev., v.
18, n.11, p.1331-1344, Jun. 2004.
THIBODEAU, S. N. et al. Altered expression of
hMSH2 and hMLH1 in tumors with microsatellite
instability and genetic alterations in mismatch repair
genes. Cancer Res., v. 56, n. 21, p. 4836-4840, Nov.
1996.
UEHARA, H. et al. Deficiency of hMLH1 and hMSH2
expression is a poor prognostic factor in esophageal
squamous cell carcinoma. J. Surg. Oncol., v. 92, n.2,
p.109-115, Nov. 2005.
UMAR, A. et al. Requirement for PCNA in DNA
mismatch repair at a step preceding DNA resynthesis. Cell, v. 87, n.1, p.65-73, Oct. 1996.
UMAR, A.; KUNKEL, T. A. DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur.J.Biochem., v. 238, n. 2, p. 297-307, Jun.1996.
YAN, T. et al. DNA mismatch repair (MMR) mediates 6-thioguanine genotoxicity by introducing single-strand breaks to signal a G2-M arrest in MMRproficient RKO cells. Clin.Cancer Res., v. 9, n. 6, p.
2327-2334, Jun. 2003.
YOUN, C. K. et al. Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity. Nat.Cell Biol., v. 7, n. 2, p. 137-
147, Feb. 2005.
ZEKRI, A. R. et al. Mismatch repair genes (hMLH1,
hPMS1, hPMS2, GTBP/hMSH6, hMSH2) in the
pathogenesis of hepatocellular carcinoma. World
J.Gastroenterol., v. 11, n. 20, p. 3020-3026, May. 2005.
ZENG, M. et al. Ionizing radiation-induced apoptosis via separate Pms2- and p53-dependent pathways.
Cancer Res., v. 60, n. 17, p. 4889-4893, Sep. 2000.
ZHANG, H. et al. Apoptosis induced by overexpression of hMSH2 or hMLH1. Cancer Res., v. 59, n. 13,
p. 3021-3027, Jul. 1999.
ZHANG, Y. et al. Reconstitution of 5'-directed human mismatch repair in a purified system. Cell, v.
122, n. 5, p. 693-705, Sep. 2005.
ZIENOLDDINY, S. et al. Msh2 deficiency increases
susceptibility to benzo[a]pyrene-induced lymphomagenesis. Int.J.Cancer, v. 118, n. 11, p. 2899-2902,
Jun. 2006.
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2020-05-04
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MACEDO DE OLIVEIRA, M. V. .; DE CARVALHO FRAGA, C. A. .; SENA GUIMARÃES, A. L. . Complexos de reparo mismatch: mecanismos e funções. Revista Unimontes Científica, [S. l.], v. 11, n. 1/2, p. 31–36, 2020. Disponível em: https://www.periodicos.unimontes.br/index.php/unicientifica/article/view/2273. Acesso em: 26 abr. 2024.
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