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p53: traffic cop at the crossroads of DNA repair and recombination

Key Points

  • The transcription-independent function of p53 facilitates DNA repair and controls recombination.

  • p53 modulates nucleotide-excision repair (NER) by transactivating repair-specific genes p48DDB2 and xeroderma pigmentosum complementation group C (XPC); p48DDB2 is involved in the transportation of XPC to the sites of DNA damage. p53 also influences the activities of XPB and XPD helicases, and possibly functions as a chromatin-accessibility factor.

  • p53 facilitates base-excision repair (BER) mainly via association with BER components. For example, the in vivo interaction of p53 with APE1/REF1 and DNA polymerase β enhances BER.

  • p53 can regulate mismatch repair (MMR) by transactivating the MSH2 gene and forming multi-functional complexes involving repair-specific (MSH2 and MSH6) and recombination (such as RAD50 and RAD51) proteins.

  • Wild-type p53 protein might inhibit error-prone, but not error-free, NHEJ. p53 can control homologous recombination (HR) in vitro by specific recognition of the heteroduplex intermediates, and in vivo by modulating the functions of different HR-specific proteins.

  • RecQ-family helicases and p53 have functional inter-regulatory relationships during HR. For example, the Bloom's syndrome (BLM) helicase enhances p53 accumulation at the sites of stalled replication forks in vivo.

Abstract

p53 mutants that lack DNA-binding activities, and therefore, transcriptional activities, are among the most common mutations in human cancer. Recently, a new role for p53 has come to light, as the tumour suppressor also functions in DNA repair and recombination. In cooperation with its function in transcription, the transcription-independent roles of p53 contribute to the control and efficiency of DNA repair and recombination.

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Figure 1: p53 functions as a 'molecular node' in the DNA-damage response.
Figure 2: Role of p53 in nucleotide-excision repair.
Figure 3: Role of p53 in base-excision repair.
Figure 4: Role of p53 in homologous recombination.

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Acknowledgements

We thank J. Bradsher, X. Wang, J. Shen and S. Linke for helpful discussions. We also thank D. Dudek for editorial assistance and K. MacPherson for bibliographic assistance.

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Correspondence to Curtis C. Harris.

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DATABASES

Entrez

BLM

RECQ4

Terc

WRN

OMIM

Bloom syndrome

HNPCC

Rothmund–Thomson syndrome

Werner syndrome

Xeroderma pigmentosum

Swiss-Prot

APE1

ATM

ATR

ATRIP

CHK2

CSA

CSB

DNA ligase IV

Jun

Ku70

Ku80

MDM2

MLH1

MSH2

MSH6

p48DDB2

p53

p127DDB1

PCNA

PMS2

RAD23B

RAD51

RAD52

Sp1

XPA

XPB

XPC

XPD

XPF

XRCC4

Glossary

MISMATCH REPAIR

(MMR). A DNA-repair process that removes mispaired nucleotides and insertion or deletion loops.

NUCLEAR MATRIX

A network of nuclear proteins that provides a structural framework for organizing chromatin.

NUCLEOTIDE-EXCISION REPAIR

A DNA-repair process in which a small region of the DNA strand that surrounds the UV-induced DNA damage is recognized, removed and replaced.

BASE-EXCISION REPAIR

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

NON-HOMOLOGOUS END-JOINING

The main DNA-repair pathway that is used throughout the cell cycle to repair chromosomal DSBs in somatic cells. NHEJ is error-prone because it leads to the joining of the breaks without a template.

HOMOLOGOUS RECOMBINATION

A DNA-recombination pathway, which includes the repair of DSBs, and which uses a homologous double-stranded-DNA molecule as a template for the repair of the broken DNA.

CYCLOBUTANE PYRIMIDINE DIMER

(CPD). The main UV-induced lesion that functions as a structural block for transcription and replication.

(6-4) PHOTOPRODUCT

A type of DNA lesion that accounts for one quarter of all the DNA distortions and that are produced by moderate doses of UV irradiation.

CHROMATIN-ACCESSIBILITY FACTOR

A factor that allows the detection and subsequent removal of bulky DNA adducts by 'opening' the chromatin.

MICROSATELLITE INSTABILITY

A mutational change that occurs in the DNA, in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different from the number of repeats that were in the DNA when it was inherited.

V(D)J REARRANGEMENTS

The process of rearrangement and fusions of variable gene (V), diversity gene (D) and joining gene (J) segments that generate functional immunoglobin genes.

HETERODUPLEX

A DNA duplex formed by the association between two homologous strands, each of which was previously hybridized to different complementary strands. If the homology is less than 100%, the heteroduplex will contain base mismatches that will require repair.

HOLLIDAY JUNCTION

A cruciform DNA structure that is generated during the synaptic phase of homologous recombination.

RECQ HELICASE

A family of evolutionarily conserved helicases, mutations of which can lead to hereditary cancer-predisposition syndromes in humans.

SISTER-CHROMATID EXCHANGE

An event that is similar to crossing over and that can occur between sister chromatids at mitosis or at meiosis.

QUADRIRADIAL

A cytogenetic aberration involving symmetrical and asymmetrical interchanges between chromatids.

CROSSING OVER

A reciprocal exchange of genetic information.

TOPOISOMERASE

A class of enzymes that are involved in the regulation of DNA supercoiling.

IONIZING RADIATION

Radiation, such as X-rays and γ-rays (high-energy photons), that causes atoms to release electrons and become ions.

PML NUCLEAR BODY

(PML NB). One type of nuclear speckle that contains several proteins, including the promyelocytic leukaemia protein (PML). It is thought to be the site of recruitment of various proteins and might also have a role in gene transcription.

ANEUPLOIDY

The ploidy of a cell refers to the number of chromosome sets that it contains. Aneuploid karyotypes are chromosome complements that are not a simple multiple of the haploid set.

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Sengupta, S., Harris, C. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol 6, 44–55 (2005). https://doi.org/10.1038/nrm1546

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