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Who's on first in the cellular response to DNA damage?

Nature Reviews Molecular Cell Biology volume 4, pages 361–373 (2003)Cite this article

Key Points

  • Recognition and repair of damaged DNA is essential for genomic stability in all living cells.

  • There are several pathways of DNA repair and, for some types of damage, repair pathways might compete, or alternative pathways might operate.

  • Cellular proteins with other functions might also bind DNA lesions and influence repair.

  • The DNA-damage response is much more than simply the elimination of damage. It also involves the control of when, where and how repair should be accomplished.

  • The ultimate outcome for the cell, and for the organism of which it is a part, might depend on which protein first encounters and binds at the damaged region of DNA.

Abstract

Cellular DNA-repair pathways involve proteins that have roles in other DNA-metabolic processes, as well as those that are dedicated to damage removal. Several proteins, which have diverse functions and are not known to have roles in DNA repair, also associate with damaged DNA. These newly discovered interactions could either facilitate or hinder the recognition of DNA damage, and so they could have important effects on DNA repair and genetic integrity. The outcome for the cell, and ultimately for the organism, might depend on which proteins arrive first at sites of DNA damage.

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Figure 1: Excision repair pathways for DNA damage.
Figure 2: Consequences of 'who's on first' in DNA-damage recognition.
Figure 3: Consequence 1 — facilitation of repair.
Figure 4: Consequence 2 — interference with repair.
Figure 5: Consequence 3 — redirection of damage processing.

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Acknowledgements

We would like to thank A. Ganesan and C. A. Smith for their helpful discussions, and the National Institutes of Health for supporting our research. In addition, we would like to acknowledge the referees for their insightful comments.

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Authors and Affiliations

  1. Department of Biological Sciences, Stanford University, 371 Serra Mall, Stanford, 94305-5020, California, USA

    Susan D. Cline & Philip C. Hanawalt

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  1. Susan D. Cline
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Correspondence to Philip C. Hanawalt.

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DATABASES

OMIM

ATR

BRCA1

HMG1

MLH1

MSH2

mtTFA

SPTAN1

SRY

topoisomerase

YB-1

Saccharomyces Genome Database

Ixr1

Nhp6A

Nhp6B

Phr1

Top1

Top2

Top3

FURTHER INFORMATION

Philip C. Hanawalt's laboratory

DNA repair interest group

Human DNA repair genes

Protein Data Bank

Glossary

EXCISION REPAIR

A process for repairing chemical damage, mismatches or small loops in DNA, in which a single-stranded section containing the aberrant structure is removed and the resulting gap is filled by DNA replication that is templated from the complementary strand.

BASE EXCISION REPAIR

(BER). The replacement of DNA bases that are altered by small chemical modifications through the excision of only the damaged nucleotide (short-patch BER) or through the removal of 2–13 nucleotides containing the damaged nucleotide (long-patch BER).

NUCLEOTIDE EXCISION REPAIR

(NER). The replacement of DNA bases that are altered by large chemical additions or cross-links through the excision of a short, single-stranded segment containing the damage.

MISMATCH REPAIR

(MMR). An excision repair pathway that identifies and corrects mispaired bases and 1–3-nucleotide loops that result from DNA polymerase errors during replication.

DNA GLYCOSYLASE

An enyzme that binds selectively to a damaged DNA base and hydrolyses the N-glycosylic bond to release the altered base from the sugar–phosphate backbone leaving an abasic site.

AP LYASE

A nicking activity that is associated with some DNA glycosylases, which cuts the DNA strand on the 3′-side of an abasic site leaving a 5′-phosphate and a 3′-fragmented deoxyribose.

AP ENDONUCLEASE

An enzyme that binds an abasic site and creates a nick on the 5′-side, yielding a 3′-hydroxyl and a 5′-abasic sugar phosphate. AP endonucleases also have a 3′-diesterase activity, which can nick 5′ of the abasic deoxyribose remaining after AP lyase activity.

DNA POLYMERASE

An enzyme that replicates a DNA strand using the complementary DNA strand as a template. DNA polymerase β replaces the nucleotide removed in short-patch BER. Several DNA polymerases, including α, β, δ and ε, might be involved in long-patch BER.

XERODERMA PIGMENTOSUM

(XP). An hereditary disorder arising from defects in genes from seven complementation groups (XPA–XPG), which are involved in the early steps of the nucleotide excision repair pathway, and an eighth group, XPV, with mutations in the translesion DNA polymerase η.

COCKAYNE'S SYNDROME

(CS). An autosomal-recessive disease that is characterized by neural and skeletal-development abnormalities and severe photosensitivity, but with no cancer-predisposition phenotype. Cell lines derived from these patients are defective in transcription-coupled DNA repair.

REPLICATION PROTEIN A

(RPA). A three-subunit complex that binds single-stranded DNA and is required for initiation from origins of replication and nascent DNA synthesis. RPA also functions in NER.

TFIIH

A basal transcription factor complex of nine subunits that includes the XPB and XPD helicases, which are necessary for its function in DNA repair.

TRANSCRIPTION-COUPLED REPAIR

(TCR). A dedicated pathway for the excision repair of DNA damage in the transcribed strand that arrests the translocating RNA polymerase.

DNA PRIMASE

An enzyme that synthesizes short RNA sequences used as primers for lagging-strand DNA synthesis by the DNA polymerase.

CISPLATIN

A platinum-containing drug that is used in cancer therapy and forms intra- and interstrand cross-links between DNA bases, of which the primary adducts are intrastrand-1,2-d(GpG) and 1,2-d(ApG).

HIGH-MOBILITY-GROUP (HMG) BOX

A minor-groove DNA-binding domain that is found in proteins with various cellular functions.

TATA-BINDING PROTEIN

(TBP). A protein that binds to the minor groove of the TATA-box sequence of gene promoters to initiate transcription.

Y-BOX-BINDING PROTEIN-1

(YB-1). A transcription factor that binds inverted CCAAT-box sequences that are found in the promoter region of many genes.

TFTC

A complex of transcription-initiation factors for RNA polymerase II that lacks TBP and can mediate transcription from both TATA-containing and TATA-less promoters.

HISTONE H1

A protein that binds to linker regions of DNA between nucleosome core particles to facilitate the folding of these particles into a 30-nm chromatin fibre and to stabilize higher-order chromosomal structure.

FANCONI ANAEMIA

(FA). A chromosomal-instability syndrome that is characterized by bone-marrow failure, congenital defects, increased cancer susceptibility and cellular sensitivity to various DNA-damaging agents.

FUROCOUMARINS

Photosensitive tricyclic compounds that can intercalate into DNA and, on activation by UVA (320–400-nm) light, can react with thymine to form monoadducts and interstrand cross-links. Primary examples are the psoralens.

SPECTRIN

A tetrameric membrane protein that associates with actin, ankyrin and calmodulin for cytoskeletal formation and secretory-vesicle transport in the cytoplasm.

SWI/SNF COMPLEX

ATP-dependent chromatin-remodelling complex, which changes the superhelical torsion of DNA in nucleosomes to regulate the transcription of genes.

ATAXIA-TELANGIECTASIA

(AT). An autosomal-recessive chromosomal instability disease that is characterized by clinical and cellular sensitivity to ionizing radiation and abnormalities in the nervous, endocrine and immune systems as well as in the skin.

CHK1 AND CHK2

Serine/threonine kinases that are believed to function downstream of ATM and ATR and to phosphorylate p53 in the cellular DNA-damage response.

PROLIFERATING CELL NUCLEAR ANTIGEN

(PCNA). A protein complex that forms a clamp on DNA and associates with DNA polymerases to increase their processivity during DNA synthesis. It also associates with RPA and DNA polymerase β during DNA repair.

DNA TOPOISOMERASES

A group of enzymes that control the superhelical density of DNA and resolve DNA topological structures through rotational and DNA-strand-passage mechanisms involving the formation of transient protein-linked DNA breaks.

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Cline, S., Hanawalt, P. Who's on first in the cellular response to DNA damage?. Nat Rev Mol Cell Biol 4, 361–373 (2003). https://doi.org/10.1038/nrm1101

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