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Réparation de l'ADN

L’ADN est le vecteur de l’information génétique constituante de tout être vivant. Le code génétique inscrit dans l’ADN est essentiel dans le processus qui va de la formation des cellules à l’apparence et aux fonctions de l’organisme dans son entier. Toutefois, l’ADN est exposé en permanence aux attaques de nature endogène telles que l’hydrolyse, l’oxydation, l’alkylation, ou les erreurs de réplication. De plus, les radiations ionisantes, les UV, et une pléthore d’agents chimiques constituent des facteurs externes qui menacent l’intégrité de l’ADN.

Contrairement à l’ARN et aux protéines, l’ADN n’est pas dégradé puis re-synthétisé une fois endommagé. En revanche, différentes voies de réparation existent afin de garantir que l’ADN reste intact. En 1974, Francis Crick a fait remarquer que « nous avons complètement négligé le rôle éventuel des enzymes dans la réparation [de l’ADN]. Puis j’en suis venu à la conclusion que l’ADN est tellement précieux qu’il existe probablement de nombreux mécanismes différents. »

Aujourd’hui, cette prédiction s’avère vraie : plus d’un millier de gènes impliqués dans un réseau imbriqué de voies de réparation de l’ADN ont été identifiés depuis. Les dégâts subis par l’ADN peuvent être réparé par l’intermédiaire de six voies différentes, en fonction de la nature de la lésion : les remèdes aux modifications chimiques, aux nucléotides mal incorporés et aux liaisons transversales sont la réparation directe (DR), la réparation par mésappariement (MMR), et la réparation par excision de nucléotides. Les cassures d’un seul brin d’ADN sont réparées grâce à une excision de base. Puis les cassures de doubles brins d’ADN, hautement mutagènes, sont réparées grâce à plusieurs voies complexes qui consistent en une recombinaison homologue (HR) avec les chromatides-sœurs (lors de la phase S ou G2 du cycle cellulaire) ou en une réparation par jonction d'extrémités non homologues (NHEJ) des deux extrémités de la cassure des doubles brins. Lorsque la lésion subie par l’ADN ne peut pas être réparée rapidement, des ADN polymérases spécialisés permettent une synthèse de translésion (TLS) destiné à empêcher la fourche de réplication de l’ADN d’être paralysée. Les mutations qui rendent inopérants les éléments de ces voies de réparation provoquent des maladies telles que le xeroderma pigmentosum, l’ataxie télangiectasie, l’anémie de Fanconi, ainsi qu’une prédisposition au cancer.

Par ailleurs, ces mécanismes de réparation sont d’un intérêt capital pour les approches actuelles d’édition ciblée du génome qui, habituellement, tirent parti de ce mécanisme de réparation cellulaire de l’ADN.

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Canonical Non-Homologous End-Joining

PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide):

This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.[provided by RefSeq, Jul 2010].   More...

XRCC6 - X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 6

XRCC5 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 5 (Double-Strand-Break Rejoining)):

ATR (Ataxia Telangiectasia and Rad3 Related):

XRCC4 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 4):

POLL (Polymerase (DNA Directed), lambda):

MRE11A - MRE11 Meiotic Recombination 11 Homolog A (S. Cerevisiae):

Microhomology-Mediated End-Joining

PARP1 (Poly (ADP-Ribose) Polymerase 1):

This gene encodes a chromatin-associated enzyme, poly(ADP-ribosyl)transferase, which modifies various nuclear proteins by poly(ADP-ribosyl)ation. The modification is dependent on DNA and is involved in the regulation of various important cellular processes such as differentiation, proliferation, and tumor transformation and also in the regulation of the molecular events involved in the recovery...   More...

LIG2 - Ligase II, DNA, ATP-Dependent:

ATR (Ataxia Telangiectasia and Rad3 Related):

RBBP8 - Retinoblastoma Binding Protein 8:

MRE11A - MRE11 Meiotic Recombination 11 Homolog A (S. Cerevisiae):

RECQL2 - RECQL2 (ARABIDOPSIS RECQ HELICASE L2), 3'-5' DNA Helicase/ ATP-Dependent Helicase/ Four-Way Junction Helicase/ Protein Binding:

Homologous Recombination

RAD51 (DNA Repair Protein Homolog 1):

The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with the ssDNA-binding protein RPA and RAD52, and it is thought to play roles in homologous pairing and strand transfer of...   More...

POLE (Polymerase (DNA Directed), Epsilon, Catalytic Subunit):

POLE2 - Polymerase (DNA Directed), epsilon 2 (p59 Subunit):

POLE3 - Polymerase (DNA Directed), epsilon 3 (p17 Subunit):

POLE4 (Polymerase (DNA-Directed), epsilon 4 (p12 Subunit)):

POLD1 - Polymerase (DNA Directed), delta 1, Catalytic Subunit 125kDa:

POLD2 (Polymerase (DNA Directed), delta 2, Accessory Subunit):

POLD3 - Polymerase (DNA-Directed), delta 3, Accessory Subunit:

POLD4 (Polymerase (DNA-Directed), delta 4, Accessory Subunit):

ATR (Ataxia Telangiectasia and Rad3 Related):

XRCC2 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 2):

XRCC3 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 3):

BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1):

RBBP8 - Retinoblastoma Binding Protein 8:

FAM175A - Family with Sequence Similarity 175, Member A:

MRE11A - MRE11 Meiotic Recombination 11 Homolog A (S. Cerevisiae):

TOP3A (Topoisomerase (DNA) III alpha):

RMI2 (RMI2, RecQ Mediated Genome Instability 2, Homolog (S. Cerevisiae)):

DNA2 (DNA Replication Helicase 2 Homolog (Yeast)):

RECQL2 - RECQL2 (ARABIDOPSIS RECQ HELICASE L2), 3'-5' DNA Helicase/ ATP-Dependent Helicase/ Four-Way Junction Helicase/ Protein Binding:

MUS81 (MUS81 Endonuclease Homolog (S. Cerevisiae)):

SLX1B - SLX1 Structure-Specific Endonuclease Subunit Homolog B (S. Cerevisiae):

BTBD12 - BTB (POZ) Domain Containing 12:

GEN1 (Gen Endonuclease Homolog 1 (Drosophila)):

Single Strand Annealing

MSH3 (MutS Homolog 3 (E. Coli)):

ERCC4 - Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 4:

ATR (Ataxia Telangiectasia and Rad3 Related):

MRE11A - MRE11 Meiotic Recombination 11 Homolog A (S. Cerevisiae):

Break-Induced Replication

MCM7 - Minichromosome Maintenance Complex Component 7

MRE11A - MRE11 Meiotic Recombination 11 Homolog A (S. Cerevisiae):

Base Excision Repair

OGG1 (8-Oxoguanine DNA Glycosylase):

This gene encodes the enzyme responsible for the excision of 8-oxoguanine, a mutagenic base byproduct which occurs as a result of exposure to reactive oxygen. The action of this enzyme includes lyase activity for chain cleavage. Alternative splicing of the C-terminal region of this gene classifies splice variants into two major groups, type 1 and type 2, depending on the last exon of the...   More...

SMUG1 - Single-Strand-Selective Monofunctional Uracil-DNA Glycosylase 1:

MBD4 (Methyl-CpG Binding Domain Protein 4):

NEIL2 (Nei Endonuclease VIII-Like 2 (E. Coli)):

POLD1 - Polymerase (DNA Directed), delta 1, Catalytic Subunit 125kDa:

POLD2 (Polymerase (DNA Directed), delta 2, Accessory Subunit):

POLD3 - Polymerase (DNA-Directed), delta 3, Accessory Subunit:

POLD4 (Polymerase (DNA-Directed), delta 4, Accessory Subunit):

Nuleotide Excision Repair

POLR2B - Polymerase (RNA) II (DNA Directed) Polypeptide B, 140kDa

This gene encodes the second largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This subunit, in combination with at least two other polymerase subunits, forms a structure within the polymerase that maintains contact in the active site of the enzyme between the DNA template and the newly synthesized RNA. [provided by RefSeq, Jul 2008].   More...

ERCC2 (Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 2):

ERCC3 - DNA Repair Protein Complementing XP-B Cells:

GTF2H4 (General Transcription Factor IIH, Polypeptide 4, 52kDa):

GTF2H3 (General Transcription Factor IIH, Polypeptide 3, 34kD):

GTF2H5 - General Transcription Factor IIH, Polypeptide 5:

RFC2 (Replication Factor C (Activator 1) 2, 40kDa):

RFC3 - Replication Factor C (Activator 1) 3, 38kDa:

RFC4 (Replication Factor C (Activator 1) 4, 37kDa):

RFC5 (Replication Factor C (Activator 1) 5, 36.5kDa):

ERCC4 - Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 4:

ERCC6 (Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 6):

ERCC8 (Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 8):

POLE (Polymerase (DNA Directed), Epsilon, Catalytic Subunit):

POLE2 - Polymerase (DNA Directed), epsilon 2 (p59 Subunit):

POLE3 - Polymerase (DNA Directed), epsilon 3 (p17 Subunit):

POLE4 (Polymerase (DNA-Directed), epsilon 4 (p12 Subunit)):

XRCC1 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 1):

Mismatch Repair

(MSH2):

This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012].   More...

MSH3 (MutS Homolog 3 (E. Coli)):

MLH1 (MutL Homolog 1, Colon Cancer, Nonpolyposis Type 2 (E. Coli)):

PMS2 (PMS2 Postmeiotic Segregation Increased 2 (S. Cerevisiae)):

RFC2 (Replication Factor C (Activator 1) 2, 40kDa):

RFC3 - Replication Factor C (Activator 1) 3, 38kDa:

RFC4 (Replication Factor C (Activator 1) 4, 37kDa):

RFC5 (Replication Factor C (Activator 1) 5, 36.5kDa):

POLD1 - Polymerase (DNA Directed), delta 1, Catalytic Subunit 125kDa:

POLD2 (Polymerase (DNA Directed), delta 2, Accessory Subunit):

POLD3 - Polymerase (DNA-Directed), delta 3, Accessory Subunit:

Direct Reversal

MGMT (O6-Methylguanine-DNA-Methyltransferase):

Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. Repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O-6 position to a cysteine residue in the enzyme. This is a   More...

ALKBH - AlkB, Alkylation Repair Homolog 1 (E. Coli)

Trans-Lesion Synthesis

REV3L (REV3-Like, Polymerase (DNA Directed), Zeta, Catalytic Subunit):

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