Replicação de DNA

Preparação e Pré-requisitos para a Replicação

A replicação ocorre durante a fase S (síntese) do ciclo celular.
A duração destas fases do ciclo celular varia consideravelmente de acordo com os diferentes tipos de células. Para uma típica célula humana em proliferação rápida com um tempo de ciclo total de 24 horas, a fase G1 (crescimento) pode durar cerca de 11 horas, a fase S cerca de 8 horas, a G2 (crescimento e preparação para mitose) cerca de 4 horas e a M (mitose) cerca de 1 hora.
O DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure de uma célula humana existe na sua maioria sob a forma de 46 cromossomas (23 pares = 2n) no interior do núcleo. Uma pequena fração está presente como DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure mitocondrial, com cerca de 16.500 pares de bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance contendo 37 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure, todos essenciais para uma função mitocondrial normal.

Cell cycle, consisting of G1, S, G2, and M phases — Ciclo celular, constituído pelas fases G1, S, G2 e M
Imagem pro Lecturio.

Iniciação

Origens da replicação: Certas proteínas reconhecem secções de ADN (ricas em AT) a partir das quais a replicação pode começar.
- Os procariontes possuem apenas uma única origem de replicação.
- Os eucariontes têm múltiplas origens de replicação. No ADN humano, existem mais MAIS Androgen Insensitivity Syndrome de 30.000 origens de replicação, sem as quais a fase S duraria cerca de 40 vezes mais MAIS Androgen Insensitivity Syndrome.
Em procariontes, uma proteína chamada DnaA liga-se a uma origem de replicação. Em eucariontes, isto é realizado pelo complexo de reconhecimento de origem (ORC, pela sigla em inglês), um complexo de 6 unidades de ligação ao ADN.
A helicase DnaB dependente de ATP (procariontes) desdobra a dupla hélice do ADN → separa as 2 cadeias e expõe 2 cadeias simples.
Helicase (em eucariontes):
- Move-se ao longo da molécula de ADN na direção 5′ → 3′
- Forma o garfo de replicação usando energia da hidrólise de ATP para desfazer as pontes de hidrogénio entre as bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance de nucleótidos das cadeiras complementares, separando-as
- A síndrome de Bloom é um distúrbio de predisposição ao cancro causado por mutações no gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics da helicase BLM, 1 das quase 100 helicases presentes em humanos.
As proteínas de ligação de cadeia única (SSB, pela sigla em inglês) ligam-se às cadeias soltas → evitam que estas se voltem a ligar após a separação pela helicase.
À medida que as 2 cadeiras de ADN se desenrolam (desemaranham):
- O ADN à frente do garfo de replicação é forçado a rodar na direção oposta
- O ADN fica torcido à sua volta sem a presença de topoisomerases:
  - Catalisam a quebra reversível e união das cadeiras de ADN
  - As quebras temporárias produzidas por estas enzimas permitem que as 2 cadeiras de ADN rodem livremente, umas em torno das outras → a que a replicação possa prosseguir sem causar tensão de torção indevida no esqueleto do ADN, o que poderia levar à quebra das cadeias de ácido nucleico.
  - Em procariontes, os antibióticos de fluoroquinolona inibem as topoisomerases II (ADN girase) e IV.
  - Em eucariontes, os agentes quimioterápicos irinotecano e topotecano inibem a topoisomerase I, enquanto o etoposide Etoposide A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the g2 and s phases of the cell cycle. Microtubule and Topoisomerase Inhibitors e o teniposide Teniposide A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the g2 and s phases of the cycle. Microtubule and Topoisomerase Inhibitors inibem a topoisomerase II Topoisomerase II DNA topoisomerases that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex. Fluoroquinolones.

Replicação de DNA — A replicação ou síntese de DNA é o processo da cópia de uma molécula de DNA de cadeia dupla. Este processo é fundamental para toda a vida tal como a conhecemos.
Imagem: “DNA Replication” by Mariana Ruiz. Licença: Public Domain

Polimerase	Função	Atividade da exonuclease
α	Sintetiza o primer de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure e inicia a síntese do DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure ao longo da cadeia atrasada	3′ → 5′
β	Repara o DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure	Nenhuma
γ	Replica o DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure mitocondrial	3′ → 5′
δ	Sintetiza a cadeia atrasada, preenchendo as lacunas de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure após a remoção do primer.	3′ → 5′
ε	Sintetiza a cadeia líder	3′ → 5′ e 5′ → 3′

Alongamento

É necessário um primer para a síntese de cadeias-filha de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure.
- É um pequeno pedaço de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure (8-10 pares de bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance).
- Complementar à cadeia base
- É sintetizado pela primase (uma RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure polimerase dependente de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure)
  - Em eucariontes, é uma subunidade da DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polimerase alfa.
Síntese de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
- A replicação ocorre continuamente na cadeia líder e de forma descontínua na cadeia atrasada.
Cadeia líder
- Replicação continua devido ao grupo livre 3′ OH
- Requer apenas 1 primer
Cadeia atrasada
- Replicação descontínua para garantir sempre um grupo 3′ OH livre para alongamento
- Forma fragmentos de Okazaki (1.000-2.000 nucleótidos de comprimento)
- É necessário um primer para cada segmento de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure.
Ocorre na direção de 5′ → 3′.
Os pares de bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance são adicionados ao grupo OH do terminal 3′ da cadeia-filha.
É catalisado pela DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polimerase (polimerase δ em eucariontes e DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polimerase III em procariontes)
- Forma uma ligação éster entre o grupo 3′ OH e o grupo α-fosfato dos nucleótidos
- É libertado pirofosfato
Revisão (proofreading)
- É realizado apenas por polimerases com atividade de exonuclease de 3′ → 5′.
Remoção do primer
- Excisado no sentido oposto da síntese (i.e., 5′ → 3′)
- Procariontes: pela RNase H e pela atividade de exonuclease de 5′ → 3′ da DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polimerase I
- Eucariontes: pela FEN-1 (flap endonuclease-1)
Preenchimento das lacunas
- As lacunas são preenchidas com desoxinucleótidos complementares
- Procariontes: a DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polimerase I adiciona desoxinucleótidos um de cada vez e depois faz a revisão.
- Eucariontes: DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polimerase δ
Junção dos terminais
- O DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure ligase junta os terminais livres das cadeias-filha.
- A reação envolve:
  - A transferência de AMP para o grupo fosfato do terminal 5′.
  - O AMP é clivado e o grupo fosfato do terminal 5′ é ligado ao grupo OH do terminal 3′ de outro fragmento.
Após a duplicação do DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure, existem 46 cromossomas de cromatídio duplo (4n)
- Na anáfase e citocinese (da mitose) seguintes, os cromossomas são reduzidos a 46 de cromatídio simples (2n)

Finalização

Iniciada pela ligação de proteínas de finalização (proteínas ter) às sequências de finalização
Finalização diferente em procariontes ( DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure circular) e eucariontes (ADN linear)
Cromossomas eucarióticos → linear
- Vai existir uma lacuna.
Se durante a replicação o primer complementar estiver no terminal 5′-OH da cadeia-filha, não existe um terminal 3′-OH livre para a ligação.
A lacuna deixada pelo primer não pode ser preenchida; isto significa que, após cada replicação, falta uma pequena peça no final do ADN.
Esta é a razão para a existência de uma sequência repetitiva não-codificante (GGGTTA) com mais MAIS Androgen Insensitivity Syndrome de 10.000 pares de bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance no final do cromossoma eucariótico (telómero).
As sequências codificantes ( genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure) só deixam de ser completamente replicadas após 30-50 ciclos celulares; isto limita a esperança de vida da maioria das células somáticas.

Telómeros e Relevância Clínica

Telómeros
- Fragmentos de ADN não codificantes nas extremidades 3′ dos cromossomas.
- Cada telómero consiste em vários milhares de pares de bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance (repetições em tandem de TTAGGG)
- Função de um telómero:
  - Previne a perda de genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure estruturais
  - A cadeia atrasada torna-se mais MAIS Androgen Insensitivity Syndrome curta após cada ronda de replicação devido à remoção do primer de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure, pelo que a perda de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure ocorre no telómero em vez de nas sequências codificadorasT.
  - Funciona como um relógio celular uma vez que a célula adquire senescência replicativa ou há morte celular apoptótica quando o comprimento do telómero é menor que um limite crítico. O comprimento do DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure telomérico determina a esperança de vida da célula em cultura.
Telomerase Telomerase An essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. DNA Replication
- Uma transcriptase reversa especial que carrega o seu próprio modelo de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure
- Mantém os telómeros
- Está presente em células rapidamente divisoras, células embrionárias e células cancerígenas
  - A sua atividade é especialmente aumentada nas células cancerígenas para que os seus telómeros permaneçam longos por muito tempo e se possam continuar a dividir sem considerar um relógio molecular, mesmo que atinjam o final da sua vida normal.

Referências

Alberts, B., Johnson, A., Lewis, J., Morgan, D., Raff, M., Roberts, K., & Walter, P. (2022). Molecular biology of the cell (7th ed.). W. W. Norton & Company.
Cooper, G. M. (2019). The cell: A molecular approach (8th ed.). Sinauer Associates.
Gomes, T. M. B., Vincent, A. E., Menger, K. E., Stewart, J. B., & Nicholls, T. J. (2024). Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation. Biochemical Journal, 481(11), 683–715. https://doi.org/10.1042/BCJ20230262
Hyrien, O., et al. (2025). The double life of mammalian DNA replication origins. Genes & Development. https://doi.org/10.1101/gad.352227.124
Liu, Y., Zhangding, Z., Liu, X., & Hu, J. (2025). Chromatin-centric insights into DNA replication. Trends in Genetics, 41(5), 412–424. https://doi.org/10.1016/j.tig.2024.12.003

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Preparação e Pré-requisitos para a Replicação

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