Keeping Mammalian Mutation Load in Check: Regulation of the Activity of Error-Prone DNA Polymerases by p53 and p21

Livneh, Zvi

doi:10.4161/cc.5.17.3193

Cited by 37 publications

(24 citation statements)

References 51 publications

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“…The stimulation of recombination by p53(WT) was fully epistatic with the E3-ubiquitin ligase RAD18, which monoubiquitinates PCNA in conjunction with the E2-conjugating enzyme RAD6 (60), and with POLι, which recognizes monoubiquitinated PCNA (48). Intriguingly, it has previously been speculated that p53 is required for efficient, UV-induced PCNA monoubiquitination (39,61). The p53 effect on replication-associated recombination was partially epistatic [residual effect in cells with p53(H115N)] with the Rad5 functional homolog HLTF, which, in conjunction with UBC13/UEV1, polyubiquitinates PCNA (42), and with the translocase ZRANB3, which binds polyubiquitinated PCNA and stabilizes replication forks (45).…”

Section: Discussionmentioning

confidence: 94%

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

161

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DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonucleasedeficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linkerinduced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.T he tumor suppressor protein p53 has been called the guardianof-the-genome due to its ability to transactivate downstream targets transcriptionally, which prevents S-phase entrance before facilitating DNA repair or eliminating cells with severe DNA damage via apoptosis (1). Interestingly, p53 also encodes an intrinsic 3′-5′ exonuclease activity located within its central DNA-binding domain (2-4). The contribution of the exonuclease proficiency to p53's function has largely remained obscure. Exonucleases are involved in DNA replication, DNA repair, and recombination, increasing the fidelity or efficiency of these processes. The 3′-5′ exonuclease activity of DNA polymerases (POLs) catalyzes the correction of replication errors, thereby preventing genomic instability and cancer (5-7). The potential involvement of p53's exonuclease in DNA repair has been ascribed to transcription-independent functions in nucleotide excision repair and base excision repair, in homologous recombination (HR), and in mitochondrial processes (8-10).Regarding HR, in particular, reports indicate a dual role for p53. On the one hand, it has been reported that p53 down-regulates unscheduled and excessive HR in response to severe genotoxic stress, like formation of DNA double-strand breaks (DSBs) (8-10). This antirecombinogenic effect of p53 has been linked to the blockage of continued strand exchange by interactions with recombinase RAD51, RAD54, and nascent HR intermediates carrying specific mismatches (11, 12). On the other hand, p53 stimulates spontaneous HR during S-phase to overcome replication fork stalling and to pr...

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Section: Discussionmentioning

confidence: 94%

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

161

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“…TLS is a very localized "repair" operation, the worst outcome being a point mutation. Moreover, an elaborate regulation (22,(49)(50)(51) operates to minimize the mutagenic load caused by TLS. In contrast, HDR, despite its inherent accurate mechanism, is more complex and involves both the damaged strand and the replicated sister chromatid.…”

Section: Discussionmentioning

confidence: 99%

Genomic assay reveals tolerance of DNA damage by both translesion DNA synthesis and homology-dependent repair in mammalian cells

Izhar

Ziv

Cohen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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DNA lesions can block replication forks and lead to the formation of single-stranded gaps. These replication complications are mitigated by DNA damage tolerance mechanisms, which prevent deleterious outcomes such as cell death, genomic instability, and carcinogenesis. The two main tolerance strategies are translesion DNA synthesis (TLS), in which low-fidelity DNA polymerases bypass the blocking lesion, and homology-dependent repair (HDR; postreplication repair), which is based on the homologous sister chromatid. Here we describe a unique high-resolution method for the simultaneous analysis of TLS and HDR across defined DNA lesions in mammalian genomes. The method is based on insertion of plasmids carrying defined site-specific DNA lesions into mammalian chromosomes, using phage integrase-mediated integration. Using this method we show that mammalian cells use HDR to tolerate DNA damage in their genome. Moreover, analysis of the tolerance of the UV light-induced 6-4 photoproduct, the tobacco smokeinduced benzo[a]pyrene-guanine adduct, and an artificial trimethylene insert shows that each of these three lesions is tolerated by both TLS and HDR. We also determined the specificity of nucleotide insertion opposite these lesions during TLS in human genomes. This unique method will be useful in elucidating the mechanism of DNA damage tolerance in mammalian chromosomes and their connection to pathological processes such as carcinogenesis.error-prone DNA repair | homologous recombination repair | recombinational repair D NA damage is abundant, caused by both external agents such as sunlight and tobacco smoke and intracellular byproducts of metabolism, amounting to about 50,000 lesions per day per cell (1). Despite the presence of effective DNA repair mechanisms that eliminate lesions and restore the original DNA sequence, DNA replication often encounters unrepaired lesions that have escaped repair. These DNA damages may cause arrest of replication forks and the generation of postreplication gaps (2, 3). To complete replication and prevent the formation of double-strand breaks, which are highly deleterious, cells use DNA damage tolerance (DDT) mechanisms. These include translesion DNA synthesis (TLS) and homology-dependent repair (HDR), which enable bypass of the lesions and completion of replication, without removing the lesions from DNA. HDR uses the sequence from the intact sister chromatid to patch the single-stranded template region carrying the lesion. [We term HDR the pathways of DNA damage tolerance that rely on the homologous sister chromatid, also termed postreplication repair (PRR), damage avoidance, template switch, copy choice recombination, and homologous recombination repair.] This is carried out either by physical transfer of the segment complementary to the damaged template [also termed homologous recombination repair (HRR)] or by copying the complementary strand from the sister chromatid (template switch or postreplication repair). TLS employs specialized low-fidelity DNA polymerases to replicate across ...

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“…In keeping with this, inhibition of p21 degradation by the proteasome inhibitor MG132 completely inhibited PCNA monoubiquitination correlating with a sustained PCNA-p21 interaction ( Supplementary Figures S6A and B), which confirms that dissociation and degradation of p21 is necessary for PCNA monoubiquitination. 9,25,36 PIDD is a multifunctional protein, which is constitutively autoprocessed. Although the PIDD-C fragment triggers the RIP1-mediated NF-kB pathway, PIDD-CC sensitizes cells to apoptosis through recruitment of RAIDD/caspase-2.…”

Section: Discussionmentioning

confidence: 99%

PIDD orchestrates translesion DNA synthesis in response to UV irradiation

Logette

Schuepbach‐Mallepell²,

Eckert

et al. 2011

Cell Death Differ

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PIDD has been implicated in survival and apoptotic pathways in response to DNA damage, and a role for PIDD was recently identified in non-homologous end-joining (NHEJ) repair induced by c-irradiation. Here, we present an interaction of PIDD with PCNA, first identified in a proteomics screen. PCNA has essential functions in DNA replication and repair following UV irradiation. Translesion synthesis (TLS) is a process that prevents UV irradiation-induced replication blockage and is characterized by PCNA monoubiquitination and interaction with the TLS polymerase eta (polg). Both of these processes are inhibited by p21. We report that PIDD modulates p21-PCNA dissociation, and promotes PCNA monoubiquitination and interaction with polg in response to UV irradiation. Furthermore, PIDD deficiency leads to a defect in TLS that is associated, both in vitro and in vivo, with cellular sensitization to UV-induced apoptosis. Thus, PIDD performs key functions upon UV irradiation, including TLS, NHEJ, NF-jB activation and cell death. Cell Death and Differentiation (2011) 18, 1036-1045 doi:10.1038/cdd.2011; published online 18 March 2011 DNA lesions can result from endogenous metabolic processes as well as from exogenous DNA damaging agents. In both cases, different cellular responses are engaged (cell cycle arrest, repair pathways or apoptosis) to maintain genetic integrity. PCNA (proliferating cell nuclear antigen) acts as a DNA sliding clamp, which helps loading of replicative DNA polymerases. PCNA is involved in several forms of DNA repair, such as NER (nucleotide excision repair), BER (base excision repair) and MMR (mismatch repair), and also in other aspects of DNA metabolism, such as replication, chromatin assembly and cohesion. 1 PCNA mediates these different functions through interactions with proteins specific to each process. 2 Many of these PCNA interacting proteins (PIPs) contain a so-called PIP-box. 1,3 Competition between different partners for the same binding site on PCNA is one of the mechanisms that coordinate the functions of PCNA in DNA replication and repair. PCNA is loaded around the DNA by the conserved chaperone-like clamp loader complex RFC (replication factor C), consisting of five subunits (RFC1 to RFC5). 4,5 The RFC subunits all contain a PIP-box and thereby physically interact with PCNA. 6 Once PCNA is linked to the DNA, the RFC complex is ejected from the clamp to allow DNA polymerase access to the clamp. 7 The protein with the strongest affinity for PCNA is the PIPbox containing p21 (Cip1/Waf1), 8 a potent cyclin-dependent kinase (CDK) inhibitor involved in cell cycle regulation, except in response to UV, where cell cycle arrest is independent of p21. 9 P21 binds to PCNA and inhibits its activity, 10,11 mainly because p21 obstructs the interaction of PCNA with DNA replication and repair factors. [12][13][14][15] In vitro studies have shown that p21 also inhibits the loading of PCNA onto DNA, 7 thereby compromising DNA repair. 9 UV is one of the major exogenous sources of DNA damage. The most common...

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Keeping Mammalian Mutation Load in Check: Regulation of the Activity of Error-Prone DNA Polymerases by p53 and p21

Cited by 37 publications

References 51 publications

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Genomic assay reveals tolerance of DNA damage by both translesion DNA synthesis and homology-dependent repair in mammalian cells

PIDD orchestrates translesion DNA synthesis in response to UV irradiation

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