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Regulation of DNA repair by ubiquitylation

Nature Reviews Molecular Cell Biology volume 7, pages 323–334 (2006)Cite this article

Key Points

  • Recent studies in the DNA-repair field have highlighted the expanding role of ubiquitylation and sumoylation in the regulation of diverse DNA-repair processes and pathways such as homologous recombination (HR), nucleotide-excision repair (NER), base-excision repair (BER) and translesion DNA synthesis (TLS).

  • Fanconi Anemia (FA) proteins interact in a common pathway to monoubiquitylate the downstream effector protein, FANCD2, which enables it to functionally associate with breast and ovarian cancer suppressor proteins BRCA1 and BRCA2, and other chromatin-bound DNA-repair proteins.

  • Monoubiquitylation of the replication-processivity factor PCNA activates TLS through the interaction of novel ubiquitin-binding domains of Y-family TLS polymerases with the modified PCNA.

  • COP9 signalosome (CSN) negatively regulates the function of two existing cullin-based E3-ligase complexes, DDB2 and CSA, to promote NER.

  • Reversible polyubiquitylation of XPC upon ultraviolet (UV) irradiation alters the DNA-binding properties of XPC and the DDB complex for UV photoproducts, an important property for NER.

  • Sumoylation of the thymine-DNA glycosylase (TDG) of the BER pathway reduces the affinity of TDG for the generated abasic site, thereby allowing efficient product release from the modified DNA template.

Abstract

The process of ubiquitylation is best known for its role in targeting proteins for degradation by the proteasome. However, recent studies of DNA-repair and DNA-damage-response pathways have significantly broadened the scope of the role of ubiquitylation to include non-proteolytic functions of ubiquitin. These pathways involve the monoubiquitylation of key DNA-repair proteins that have regulatory functions in homologous recombination and translesion DNA synthesis, and involve the polyubiquitylation of nucleotide-excision-repair proteins.

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Figure 1: The regulation of the Fanconi Anemia pathway by monoubiquitylation.
Figure 2: The monoubiquitylation of PCNA by RAD6–RAD18 results in a DNA polymerase switch.
Figure 3: The regulation of nucleotide-excision repair by the polyubiquitylation of XPC.
Figure 4: The regulation of base-excision repair by SUMO1 modification of human thymine-DNA glycosylase.

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Acknowledgements

We thank I. Dikic for sharing data prior to publication, and R. Kennedy and K. Mirchandani for critical reading of the review. This work was supported by grants from the National Institutes of Health and the Doris Duke Foundation. T.T.H. is a Blount fellow for the Damon Runyon Cancer Research foundation.

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  1. Departments of Radiation Oncology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Tony T. Huang & Alan D. D'Andrea

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Correspondence to Alan D. D'Andrea.

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DATABASE

DATABASE

Fanconi Anemia

Glossary

Nucleotide-excision repair

A DNA-repair process in which a small region of the DNA strand that surrounds the DNA damage (which is predominantly induced by exposure to ultraviolet light) is recognized, removed and replaced.

Global genome repair

A nucleotide-excision repair pathway that surveys the entire genome for helix-distorting DNA damage.

Transcription-coupled repair

A nucleotide-excision repair pathway that preferentially removes lesions from the coding strands of genes that are actively transcribed by RNA polymerase II.

Base-excision repair

(BER). The main DNA-repair pathway that is responsible for the repair of apurinic and apyrimidinic (AP) sites in DNA. BER is catalysed in four consecutive steps: a DNA glycosylase removes the damaged base; an AP endonuclease (APE) processes the abasic site; a DNA polymerase inserts the new nucleotide(s); and DNA ligase rejoins the DNA strand.

Mismatch repair

A DNA-repair process that removes mispaired nucleotides and insertion/deletion loops.

Homologous recombination and non-homologous end joining

(HR and NHEJ). The main pathways for the repair of DNA double-strand breaks (DSBs). Whereas HR relies on the presence of stretches of homologous, intact, double-stranded DNA as a template, NHEJ joins and seals DSBs together more indiscriminately. Especially after DNA replication when a second identical DNA copy is available, HR seems to be the preferred pathway to deal with DSBs. Otherwise, cells tend to rely on NHEJ, which is more error-prone.

Translesion DNA synthesis

Replicative DNA synthesis is a faithful process that employs high-fidelity DNA polymerases that cannot deal with damage in the DNA template. Most DNA lesions can block the progress of the replication fork. To overcome such blocks, the cell uses specialized low-fidelity DNA polymerases, which synthesize DNA past lesions.

Replication sliding clamp

A protein (or group of proteins) that encircles the DNA double helix and aids in the processivity of DNA replication by DNA polymerases.

BRCA1

A 220-kDa nuclear protein that responds to DNA damage by participating in cellular pathways that are responsible for DNA repair, mRNA transcription, cell-cycle regulation and protein ubiquitylation.

BRCA2

The product of the second breast cancer susceptibility gene that functions in the repair of DNA double-strand breaks and crosslinks through homologous recombination.

PHD domain

(Plant homeodomain). A zinc-binding domain that is a close structural relative of the RING domain whose function might include phosphoinositide binding, chromatin association and ubiquitin-ligase activity.

Triple-helix displacement assay

An assay for demonstrating translocase activity, as employed to test proteins with helicase domains that use the energy of ATP hydrolysis to translocate along DNA.

Checkpoint kinase ATR

A member of the phosphatidyl inositol 3-kinase-like kinase (PIKK) family that functions after DNA damage to initiate cell-cycle arrest to prevent further genomic instability. ATR responds to replicative stress, as caused by exposure to ultraviolet light or hydroxyurea. For example, it activates checkpoint kinases CHK1and CHK2, which, in turn, target other proteins to induce cell-cycle arrest and facilitate DNA repair.

RAD51

The main eukaryotic recombinase that is responsible for initiating DNA-strand exchange during homologous recombination.

TLS polymerase

(Translesion DNA synthesis polymerase). A low-fidelity polymerase that is used to bypass DNA lesions at the replication fork. Some TLS polymerases can be less error-prone than others, depending on the types of lesions encountered.

Metalloprotease

A peptidase that requires metal-ion chelation for its enzymatic cleavage activity.

JAMM motif

The Jab1/MPN domain metalloenzyme (JAMM) motif in the Jab1/Csn5 subunit of the COP9 signalosome (CSN), which underlies the NEDD8-isopeptidase activity of CSN. Almost all JAMM domains possess a His-X-His-X10-Asp motif (where X indicates any residue) accompanied by an upstream conserved Glu residue.

Cullin-based ubiquitin ligases

A superfamily of ubiquitin ligases that is characterized by an enzymatic core that contains a cullin-family member and a RING-domain protein.

SCF-type ubiquitin ligases

A multisubunit ubiquitin ligase (E3) complex that consists of SKP1, CUL1 and an F-box protein that confers substrate specificity, and a RING-domain protein, such as RBX1 or ROC1.

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Huang, T., D'Andrea, A. Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol 7, 323–334 (2006). https://doi.org/10.1038/nrm1908

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