A list of Genes That Repair DNA Damage:

 

(The list is not complete)

 

Bacterial genes:

 

UVR-A:  Mutant is highly sensitive to UV, it is an ATPase subunit of an endonuclease, inhibits cell division if DNA replication is not completed or DNA repair has not been completed; it initiates the removal of Thymidine and other dimers.

 

·         UVR-B: A dimer, a subunit of an endonuclease, involved in the removal of T-T or C-T dimers.

 

UVR-C: Monomer, subunit of an endonuclease, involved in removal of dimers.

 

·         UVR-D: A monomer, acts as a DNA helicase-II, helps in unwinding and removal of cut strands, also involved in error prone repair.

 

Rec-A: mutation affect recombination, does not induce repair pathway after damage, Mol.wt is 38 KD, monomer, has protease activity, involved in DNA strand exchange in recombination repair mechanism, initiates SOS repair pathway.

 

·         Rec-B: Mutation affects recombination, It is an Exo-V ATPase, used in recombination repair (Rec-BCD=330 kd).

 

Rec-C: Mutation affects recombination repair, it is an Exo-V, and it has DNA binding property, involved in recombination repair property.

 

·         Rec-D: Mutant affect recombination repair, it is an exo-V protein, 58kd Mol.wt, involved in recombination repair.

 

Rec-F: Mutants affect recombination repair, protein unknown, and function not known.

·         Rec-J: mutants affect the function of rec-BC, sbc-B function.

 

Rec-NoR: same as rec-F, it is the part of rec-F recombination pathway.

 

·         Rec-Q: involved in recombination repair pathway, it has DNA helicase and ATPase activity.

 

Red-E: mutants affect recombination; it is an Exo-VIII function.

 

·         Phr: Photolyase (DRPP), mutants fail to repair dimers, (potential cause for skin cancer, and Xeroderma pigmentosa in Humans, Mol.wt is 55-65 KD, it has a chromophore, activated by 300 to 600nm light waves, and it binds to dimer lesion and makes them monomers.

 

Spc-B: suppresses rec-BC mutation, it has Exo-I function; it has both 5’-3’ and 3’-5’ exonuclease activities.

 

·         Dam: UV sensitive, it is s-Adenosyl methylase, methylates A in GATC sequence, helps in identifying old strand, before methylation.

 

Mut-D: (Dna-R), epsilon subunit of DNA POL-III, it has 3’-5’exonuclease activity and perform direct proof reading activity.

 

·         Mut-C: MutCand Mut A are homologues; involved in novel mechanism of mutagenesis.

 

Mut-H: it is an endonuclease dam mediated, component of mismatch repair system, acting on newly formed DNA strand.

 

·         Mut-L: MutL also has weak ATPase activity (it uses ATP for purposes of movement). It forms a complex with MutS and MutH, increasing the MutS footprint on the DNA

 

Mut-S: both recognize mismatch pair remove C=T base pairing.

 

·         Mut-U: it is same as Uvr-D and it is a DNA helicase, (mut-C, H, L, S and mut-U are all involved in mismatch repair.

Mut-Y: mutants increase mutational frequency in other genes, it has

Adenine Glycosylase activity, excises A from A=G or A=C pairing.

 

Ada: Mutants make cells sensitive to alkylation, increase mutation rates; it has guanine methyl transferase activity, removes CH3 group from Guanine on to its surface. Also removed CH3 from p-s-p backbone.

 

·         Alk-A: sensitive to alkylation, it is a methyl adenine glycosylase, removes CH3 from adenine and guanine.

 

Umu-C: reduces mutagenic effects of error prone repair, protein is not known, and exact function is not known.

 

·         Umu-D: It helps in mutagenic bypass.

 

Lon: mutants are UV sensitive, septation defective, it has ATP-dependent protease activity and binds to DNA, may control genes for capsular polysaccharides.

 

·         Ung: mutants increase the frequency of mutation; it removes deaminated cytosine or Uracil by breaking it glycosidic bonds.

 

Him-A: subunit of an integration factor, involved in site-specific recombination.

 

·         Sox-R: it is an exo-IV.

 

Kat-F: it is an exo-III.

 

·         Sfi-A and Sfi-B; inhibit cell division.

 

Ruv-A: 37kd, it is involved in ATP driven branch migration during recombination.

 

·         Ruv-B: 22kd binds to Holiday junction.

 

Ruv-C: 19kd, nuclease cuts at junctions.

 

·         Din-A, B, D, I: damage inducible genes (din = him).

Super family of DNA Polymerases:  dinB and umu CD code for DNAP-IV and V respectively,

 

Eukaryotic genes:

 

Yeast:

Yeast has ten-radiation sensitive mutants involved DNA repair process.

RAD-3 group: Involved in excision repair; a component of transcriptional complex. This group of factors remove any damage or impediment in transcriptional strands for fair transcription.

RAD-6 group: Involved in post replication repair.

RAD-52 group: Group 1- involved in homologous recombination repair;  the genes are RAD50, RAD51, Rad54, RAD 55, and RAD 57. 

Group-II: involved in non-homologous recombination , genes involved are- RAD50, MRE11 and XRS2.

Rad30: DNA pol-h, this enzyme introduces A-A pair against T-T pair.

 

Yeast Genes Involved in Homologous recombination:

Rad50: DNA dependent ATPase; processing DNA ends to generate sticky tails for base paring.

RAD51: Strand exchange homologues similar to E.coli RecA.

Rad52: Annealing homologous DNA ends; but complexed with RD1.

Rad54: Possible helicase? !

Rad55: It gas as role in augmenting strand exchange, performs with complexed to RAD55.

SSb: single strand binding protein in E.coli, it facilitates strand exchange, in recombination.

 

Nucleotide Excision Repair Genes:

Yeast genes versus Human genes:

Yeast:    Human:

RAD1:               ERCC$(XPF?)

RAD2:               XPG

RAD4    XPC

RAD10  ERCC1

Rad14:   XPA

RAD23  HHR23A

HHR23B

Yeast Genes:

Nucleotide excision Homologous recombination, Damage bypass:

Repair                                    Repair                                                            Repair

 

RAD3                         RAD52                                               RAD6

RAD1                         RAD50                                               RAD5

RAD2                         RAD51                                               RAD6

RAD3                         RAD52                                               RAD18

RAD4                         RAD53                                               RAD30

RAD7                         RAD54                                               REV1

RAD10                       RAD55                                               REV3

RAD14                       RAD56                                               REV7

RAD16                       RAD57                                               MMS2

                                                                                                UBC13

                                                                                                POL-d

                                                                                                PCNA

                                                                                                SRS2

Nucleotide Excision Repair in Eukaryotes:

Yeast Genes                          Human Genes

 

RAD1                                     ERCC4 (?XPF)

RAD2                                     XPG

RAD3                                     XPD

RAD4                                     XPC

RAD10                                   ERCC1

RAD14                                   XPA

RAD23                                   HHR23A

                                                HHR23B

 

 

Human mismatch repair:

MutS a                       MSH2-MSH6             Binds to base mismatches,

MutS b                       MSH2-MSH3             binds to insertion-deletions

MutL a                       MLH1-PMS2             early step before excision

 

 

 

 

Genes Induced as a part of SOS in E.coli.

PolB(dinA)                subunit of DNA pol II, required for recombination repair.

uvrA                           Part of ABC Excinuclease; subunits-UvrA, UvrB.

uvrB                           Part of the ABC Excinuclease.

umuC             encode DNA pol-V

umuD                        part of DNA pol-V

sulA                            encodes protein that delays cell division for repair.

RecA                           involved in error prone and recombination repair.

dinB                           encodes DNA pol-IV

 

ssb                              ssDNA binding protein

uvrD                           encoded DNA helicase.

himA                          encodes a subunit of IHF,

recN                            required for recombination repair.

dinD and dinF          functions not known                                   

 

 

 

 

Yeast genes equivalent to Human-Xeroderma pigmentosum genes:

 

            Human                      Yeast                          Functions

1.              XPA/RPA-                 Rad14/Rpa,   binds damaged DNAs 1000 fold affinity.

2.                  XPB-                           Rad 25 (SSL2),           DNA helicase component of TF-IIH.

3.      XPC/hHR23B-           Rad4/Rad23,             binds damaged DNA.

4.      XPD-                           Rad3,              DNA helicase 5’…3’, component of TF-IIH.

5.      XPE/p48- ---   ?’                                 Binds damaged DNA with 500K preference.

6.      XPF/ERCC1-                         Rad1/Rad10,             DNA endonuclease for 5’side of the damage.

7.      XPG-                           Rad2,              DNA endonuclease from 3’ side of the damage.

 

Non-homologous dsDSB-Repair Genes:

Non homologous dsDSB-Repair Genes (DBS=double strand break). They are also called NHEJ (non-homologous end joining) genes.

 

Genes-XRCC5,XRCC6:  Proteins  Ku86/Ku70; bind to DNA ends without any sequence specificity, the recruit DNA-PK ( protein kinase).

Genes-XRCC7: They are DNA-PKs, DNA dependent protein kinase, hey are serine/Threonine protein kinases but activated by DNA broken ends.

Genes-XRCC4: Ligase IV; as a dimer involved in ligation of Broken dsDNA ends.

 

Oxidative Damages;

Mitochondrial oxidative reactions generate free radicals and reactive oxygen species (-2O).

·         O2-superoxide.

·         H2O2-hydrogen peroxide.

·         OH- Hydroxyl ions.

Such oxidative components can cause  single strand breaks.

They can also cause damages to bases. Such as 8-oxyguanine, thymine glycol; however cells do contain specific glycolyases to repair such damaged bases.

 

Pyrimidine repair system (higher forms):

Xp-A; damage recognition protein, binds to damaged DNA.

Xp-B (ERCC3): It has DNA helicase activity; it is also a subunit of transcriptional factor TF-II H.

Xp-C: interacts with general transcriptional factor of TF II-H.

Xp-D (ERCC2); it is DNA helicase activity; it is a subunit of transcriptional factor TF II-H.

Xp-F; nuclease activity (excinucleases cuts at 5’of the site).

Xp-G: it has nuclease activity, cuts at 3’ of the site of lesion.

ERCC1: it is an excision repair component.  It is the part of nuclease activity, binds to XPF and replication protein RPA.

HSSB (RPA): Binds to Xp-F-ERRCC 1 complex and together with Xp-A binds to the lesion site52 and RAD6; where RAD 3 is involved in Nucleotide excision and repair; RAD52 is involved in homologous Recombination repair; and RAD6 IS INVOLED IN Damage bypass etc.

RAD3: Involved in Excision repair.

Xps:  They are a group of seven complementing genes involved in UV-damage repair system.  Cockayne syndrome is due to the defect in Xp-B, XP-D, and Xp-G and another two genes.

 

Mismatch repair in human systems:

Mut S-a: MSH2-MSH6- heterodimers; binds base to base mismatches-insertion-deletion types.

MutS b: MSH2-MSH3; binds insertion-deletion mismatched nucleotides.

MutLa: MSH1-PMS2; early step before excision of nucleotides

Note:  In E.coli the hemi-methylation directs repair components to the opposite strand where mismatch is found.  But in humans the direction to specific strand is not known.

 

In some regions, failure to repair mismatch error can lead to Colo-rectal cancer, a hereditary nopolposis colorectal cancer (HNPCC).

 

Human Disease and the Repair of UV damage:

 

Cell type

Global genomic repair

Transcription coupled repair

UV sensitivity

Skin cancer

Wild type (human)

Yes

Yes

No

no

XP groups-A,B,D,F,G

No

No

Yes

yes

CS group A,B

Yes

No

yes

no

XP group C

No

Yes

Yes

yes

XpGroup E

No for CPDs

yes

mild

yes

Wild type rodents

No for CPDs

Yes

No

yes