DNA Reparatur
Die DNA ist Träger der genetischen Information, durch die jedes Lebewesen definiert wird. Der in der DNA festgelegte genetische Code ist ein wesentlicher Bestandteil von Prozessen auf subzellulärer Ebene bis hin zur Erscheinung und Funktion des Organismus als Ganzes. Nichtsdestotrotz ist die DNA Gefahren durch endogene Quellen wie der Hydrolyse, Oxidation, Alkylierung oder Replikationsfehlern ausgesetzt. Hinzu kommen ionisierende Strahlung, UV-Strahlung und eine Reihe chemischer Reagenzien, die externe Gefahrenfaktoren für die Integrität der DNA bilden.
Anders als die RNA und Proteine, wird die DNA infolge von Beschädigungen nicht abgebaut und wieder synthetisiert. Stattdessen bestehen zahlreiche Reparatursignalwege, die sicherstellen, dass die DNA intakt bleibt. Francis Crick stellte im Jahr 1974 fest, dass „wir die mögliche Rolle von Enzymen bei der [DNA-]Reparatur vollständig außer Acht gelassen haben. Ich habe erst später festgestellt, dass die DNA so wertvoll ist, dass mehrere separate Mechanismen beteiligt sein könnten.“
Diese Vorahnung hat sich bestätigt: Mehr als 100 Gene wurden seitdem ermittelt, die an dem komplexen Netzwerk von DNA-Reparatursignalwegen beteiligt sind. DNA-Schäden können, je nach Art der Läsion, durch sechs unterschiedliche Signalwege repariert werden: Chemische Modifizierung, Nukleotid-Fehleinbau und Vernetzungen werden durch die direkte Reparatur (DR), Mismatch-Reparatur (MMR) oder die Nukleotidexzisionsreparatur behoben. Einzelstrangbrüche der DNA werden durch die Basenexzision repariert und hochmutagene Doppelstrangbrüche schließlich durch eine Reihe komplexer Signalwege auf Grundlage der homologen Rekombination (HR) mit dem Schwesterchromatid (in der S- oder G2-Phase des Zellzyklus) oder der nicht-homologen Endverknüpfung (non-homologous end-joining, NHEJ). In dem Fall, dass eine DNA-Läsion nicht rechtzeitig repariert werden kann, ermöglichen spezielle DNA-Polymerasen die Transläsionssynthese (TLS), wodurch die Verzögerung der DNA-Replikationsgabel verhindert wird. Mutationen, die Teile dieser Reparatursignalwege außer Fuktion setzen, können Krankheiten wie Xeroderma pigmentosum, Louis-Bar-Syndrom, Fanconi-Anämie sowie einer Veranlagung zu Krebs auslösen.
Weiterhin sind diese Reparaturmechanismen von hohem Interesse für den Ansatz der gezielten Genom-Editierung, der sich die zellulären DNA-Reparaturmechanismen zu Nutzen macht.
Literaturreferenzen:
- Aparacio T et al. DNA double-strand break repair pathway choice and cancer. DNA Repair (2014) PMID 24746645
- Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen (2017) PMID 28485537
- Chaudhuri AR, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol (2017) PMID 28676700
- Bian L et al. MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment. Mol Cancer (2019) PMID 31767017
- Fang C et al. Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets. Front Cell Dev Biol (2020) PMID 32300589
- Burgess JT et al. The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer. Front Oncol (2020) PMID 32850380
Canonical Non-Homologous End-Joining
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)):
PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide):
ATM (Ataxia Telangiectasia Mutated):
TRIM29 (Tripartite Motif Containing 29):
ATR (Ataxia Telangiectasia and Rad3 Related):
H2AFX (H2A Histone Family, Member X):
XRCC4 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 4):
LIG4 (Ligase IV, DNA, ATP-Dependent):
NHEJ1 (Nonhomologous End-Joining Factor 1):
APTX - Aprataxin:
APLF (Aprataxin and PNKP Like Factor):
DCLRE1C (DNA Cross-Link Repair 1C):
PNKP (Polynucleotide Kinase 3'-Phosphatase):
DNTT - TdT:
POLL (Polymerase (DNA Directed), lambda):
POLM (Polymerase (DNA Directed), mu):
MRE11A - Mre11:
RAD50 (RAD50 Homolog (S. Cerevisiae)):
NBN - Nibrin:
TP53BP1 (Tumor Protein P53 Binding Protein 1):
Microhomology-Mediated End-Joining
PARP1 (Poly (ADP-Ribose) Polymerase 1):
LIG3 (Ligase III, DNA, ATP-Dependent):
LIG2 - Ligase II, DNA, ATP-Dependent:
PARP2 (Poly (ADP-Ribose) Polymerase 2):
LIG1 (Ligase I, DNA, ATP-Dependent):
ATM (Ataxia Telangiectasia Mutated):
TRIM29 (Tripartite Motif Containing 29):
ATR (Ataxia Telangiectasia and Rad3 Related):
RBBP8 - Retinoblastoma Binding Protein 8:
MRE11A - Mre11:
RAD50 (RAD50 Homolog (S. Cerevisiae)):
NBN - Nibrin:
WRN - RECQL2:
Homologous Recombination
RAD51 (DNA Repair Protein Homolog 1):
BRCA1 (Breast Cancer 1):
BRCA2 (Breast Cancer 2, Early Onset):
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):
ATM (Ataxia Telangiectasia Mutated):
TRIM29 (Tripartite Motif Containing 29):
ATR (Ataxia Telangiectasia and Rad3 Related):
Rad51B - RAD51 Homolog B:
RAD51C (DNA Repair Protein RAD51 Homolog 3):
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):
BARD1 (BRCA1 Associated RING Domain 1):
RBBP8 - Retinoblastoma Binding Protein 8:
FAM175A - CCDC98:
UIMC1 (Ubiquitin Interaction Motif Containing 1):
MRE11A - Mre11:
RAD50 (RAD50 Homolog (S. Cerevisiae)):
NBN - Nibrin:
TP53BP1 (Tumor Protein P53 Binding Protein 1):
RPA1 (Replication Protein A1, 70kDa):
RPA2 (Replication Protein A2, 32kDa):
RPA3 (Replication Protein A3, 14kDa):
PALB2 (Partner and Localizer of BRCA2):
TOP3A (Topoisomerase (DNA) III alpha):
RMI1 (Homolog of Yeast RecQ-mediated Genome Instability 1):
RMI2 (RMI2, RecQ Mediated Genome Instability 2):
DNA2 (DNA Replication Helicase 2 Homolog):
WRN - RECQL2:
RAD54L (RAD54-Like):
MUS81 (MUS81 Endonuclease Homolog):
SLX1B - SLX1A/GIYD2:
BTBD12 (BTB (POZ) Domain Containing 12):
GEN1 (Gen Endonuclease Homolog 1):
Single Strand Annealing
MSH2 (Mismatch Repair Protein 2):
ERCC1 (Excision Repair Cross Complementing Polypeptide-1):
MSH3 (MutS Homolog 3):
ERCC4 (Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 4):
ATM (Ataxia Telangiectasia Mutated):
TRIM29 (Tripartite Motif Containing 29):
ATR (Ataxia Telangiectasia and Rad3 Related):
MRE11A - Mre11:
RAD50 (RAD50 Homolog (S. Cerevisiae)):
NBN - Nibrin:
RPA1 (Replication Protein A1, 70kDa):
RPA2 (Replication Protein A2, 32kDa):
RPA3 (Replication Protein A3, 14kDa):
RAD52 (RAD52 Homolog (S. Cerevisiae)):
Break-Induced Replication
MRE11A - Mre11:
RAD50 (RAD50 Homolog (S. Cerevisiae)):
MCM2 (Minichromosome Maintenance Complex Component 2):
MCM7 (Minichromosome Maintenance Complex Component 7):
RAD51 (DNA Repair Protein Homolog 1):
NBN - Nibrin:
RPA1 (Replication Protein A1, 70kDa):
RPA2 (Replication Protein A2, 32kDa):
RPA3 (Replication Protein A3, 14kDa):
MCM3 (Minichromosome Maintenance Complex Component 3):
MCM4 (Minichromosome Maintenance Deficient 4):
MCM5 (Minichromosome Maintenance Complex Component 5):
MCM6 (Minichromosome Maintenance Complex Component 6):
Base Excision Repair
OGG1 (8-Oxoguanine DNA Glycosylase):
UNG (Uracil-DNA Glycosylase):
APEX1 (Apurinic/Apyrimidinic Endonuclease 1):
MPG (N-Methylpurine-DNA Glycosylase):
SMUG1 (Single-Strand-Selective Monofunctional Uracil-DNA Glycosylase 1):
TDG (Thymine-DNA Glycosylase):
MBD4 (Methyl-CpG Binding Domain Protein 4):
MUTYH (MutY Homolog (E. Coli)):
NEIL1 (Endonuclease VIII-Like 1):
NEIL2 (Endonuclease 8-like 2):
NEIL3 (Nei Endonuclease VIII-Like 3):
POLB (Polymerase (DNA Directed), beta):
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):
FEN1 (Flap Structure-Specific Endonuclease 1):
LIG1 (Ligase I, DNA, ATP-Dependent):
Nuleotide Excision Repair
POLR2B (Polymerase (RNA) II (DNA Directed) Polypeptide B, 140kDa):
XPC (Xeroderma Pigmentosum, Complementation Group C):
DDB1 (Damage Specific DNA Binding Protein 1):
XPA (Xeroderma Pigmentosum, Complementation Group A):
RAD23A (RAD23 Homolog A):
RAD23B (RAD23 Homolog B):
CETN2 (Centrin, EF-Hand Protein, 2):
DDB2 (Damage-Specific DNA Binding Protein 2, 48kDa):
ERCC1 (Excision Repair Cross Complementing Polypeptide-1):
ERCC2 (Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 2):
ERCC3 (DNA Repair Protein Complementing XP-B Cells):
GTF2H1 (General Transcription Factor IIH, Polypeptide 1, 62kDa):
GTF2H4 (General Transcription Factor IIH, Polypeptide 4, 52kDa):
GTF2H3 (General Transcription Factor IIH, Polypeptide 3, 34kD):
GTF2H5 (General Transcription Factor IIH, Polypeptide 5):
CDK7 (Cyclin-Dependent Kinase 7):
RFC1 (Replication Factor C (Activator 1) 1, 145kDa):
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):
POLK (Polymerase (DNA Directed) kappa):
ERCC4 (Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 4):
ERCC5 (DNA Repair Protein Complementing XP-G Cells):
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)):
PCNA (Proliferating Cell Nuclear Antigen):
XRCC1 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 1):
FEN1 (Flap Structure-Specific Endonuclease 1):
LIG1 (Ligase I, DNA, ATP-Dependent):
RPA1 (Replication Protein A1, 70kDa):
RPA2 (Replication Protein A2, 32kDa):
RPA3 (Replication Protein A3, 14kDa):
Mismatch Repair
MSH2 (Mismatch Repair Protein 2):
MSH3 (MutS Homolog 3):
MSH6 (MutS Homolog 6 (E. Coli)):
MLH1 (MutL Homolog 1):
PMS2 (PMS2 Postmeiotic Segregation Increased 2 (S. Cerevisiae)):
RFC1 (Replication Factor C (Activator 1) 1, 145kDa):
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):
PCNA (Proliferating Cell Nuclear Antigen):
LIG1 (Ligase I, DNA, ATP-Dependent):
RPA1 (Replication Protein A1, 70kDa):
RPA2 (Replication Protein A2, 32kDa):
RPA3 (Replication Protein A3, 14kDa):
EXO1 - Exonuclease 1:
Direct Reversal
MGMT (O6-Methylguanine-DNA-Methyltransferase):
ALKBH1 (AlkB, Alkylation Repair Homolog 1):
ALKBH2 (AlkB, Alkylation Repair Homolog 2):
ALKBH3 (AlkB, Alkylation Repair Homolog 3):
Trans-Lesion Synthesis
POLI (Polymerase (DNA Directed) iota):
POLH (Polymerase (DNA Directed), eta):
REV3L (REV3-Like, Polymerase (DNA Directed), Zeta, Catalytic Subunit):
REV1 (REV1, Polymerase (DNA Directed)):
POLK (Polymerase (DNA Directed) kappa):
PCNA (Proliferating Cell Nuclear Antigen):
FA/BRCA Pathway
BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1):
ERCC1 (Excision Repair Cross Complementing Polypeptide-1):
BTBD12 (BTB (POZ) Domain Containing 12):
FAN1 (FANCD2/FANCI-Associated Nuclease 1):
CHEK1 (Checkpoint Kinase 1):
FANCI (Fanconi Anemia Complementation Group I):
FANCA (Fanconi Anemia Group A Protein):
FANCG (Fanconi Anemia Complementation Group G):
FANCM (Fanconi Anemia Complementation Group M):
BRCA2 (Breast Cancer 2, Early Onset):
HES1 (Hes Family bHLH Transcription Factor 1):
FANCE (Fanconi Anemia, Complementation Group E):
BLM (Bloom Syndrome RecQ Like Helicase):
BRCA1 (Breast Cancer 1):
FANCL (Fanconi Anemia, Complementation Group L):
EIF2AK2 (Eukaryotic Translation Initiation Factor 2-alpha Kinase 2):
FANCC (Fanconi Anemia, Complementation Group C):
FANCD2 (Fanconi Anemia, Complementation Group D2):
FANCF (Fanconi Anemia, Complementation Group F):
FANCB (Fanconi Anemia, Complementation Group B):
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