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DNA Damage Repair

DNA is the carrier of the genetic information that defines any living being. The genetic code fixed in DNA is crucial for processes on a subcellular scale up to the appearance and function of the organism as s whole. Nonetheless, DNA is constantly exposed to insults from endogenous sources such as hydrolysis, oxidation, alkylation, or replication errors. In addition, ionizing radiation, UV radiation, and a plethora of chemical reagents are external factors that threaten the integrity of DNA.

Unlike RNA and proteins, DNA is not being degraded and re-synthesized upon damage. Instead, various repair pathways are in existence to assure that the DNA remains intact. Francis Crick noted in 1974 that “we totally missed the possible role of enzymes in [DNA] repair. I later came to realize that DNA is so precious that probably many distinct mechanisms could exist.”

This presage holds true today: over a hundred genes have been characterized since that are involved in an intricate network of DNA repair pathways. DNA damage can be repaired via six different pathways depending on the nature of the lesion: chemical modifications, misincorporated nucleotides, and cross-links are reverted through direct reversal (DR), mismatch repair (MMR), and nucleotide excision repair mechanisms. DNA single strand breaks are being mended via base excision repair. Highly mutagenic DNA double strand breaks finally are repaired through a number of complex pathways that rely on homologous recombination (HR) with the sister chromatid (in the S or G2 phase of the cell cycle) or non-homologous end-joining (NHEJ) of both ends of the double strand break. In case a DNA lesion cannot be repaired in time, specialized DNA polymerases enable trans-lesion synthesis (TLS) in order to prevent the DNA replication fork from stalling. Mutations that render components of these repair pathways non-functional lead to diseases such as xeroderma pigmentosum, ataxia telangiectasia, Fanconi anemia, and a predisposition for cancer.

Besides, these repair mechanisms are of high interest for current targeted genome editing approaches that typically take advantage of the cellular DNA repair machinery.

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):

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):

FAM175A - Family with Sequence Similarity 175, Member A:

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

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):

MCM3 (Minichromosome Maintenance Complex Component 3):

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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