Role of heteroduplex joints in the functional interactions between human Rad51 and wild-type p53

Süsse, Silke; Janz, Christine; Janus, Friedemann; Deppert, Wolfgang; Wiesmüller, Lisa

doi:10.1038/sj.onc.1203809

Cited by 58 publications

(13 citation statements)

References 88 publications

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“…83 It has been suggested that a mutation in the PTEN gene causes a downregulation of RAD51, a key protein implicated in the HR repair system. 84,85 Moreover, both copy-number high, serous-like EC and HGSOC present a mutation in the TP53 gene in more than 90% of cases. Although authors found that p53 plays multiple roles in the regulation of the HR pathway, the exact mechanisms are still unclear.…”

Section: Although Few Data Have Been Published On Thementioning

confidence: 99%

<p>PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives</p>

Musacchio¹,

Caruso²,

Pisano³

et al. 2020

CMAR

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Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors.

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Section: Although Few Data Have Been Published On Thementioning

confidence: 99%

<p>PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives</p>

Musacchio¹,

Caruso²,

Pisano³

et al. 2020

CMAR

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“…The interaction of p53 with RAD54 mainly occurs via the extreme C-terminal domain of p53 (Linke et al 2003) which is involved in sensing mispaired homologous recombination intermediates. In vitro experiments have shown that RAD51 stimulates the 3′→ 5′ exonuclease activity of p53 that targets heteroduplexes containing base mismatches (Susse et al 2000). Also, the p53-RAD51 complex inhibits branch migration after the crossing-over or postsynaptic phase of recombination (Yoon et al 2004).…”

Section: Homologous Recombination Repair and P53mentioning

confidence: 99%

Involvement of p53 in the Repair of DNA Double Strand Breaks: Multifaceted Roles of p53 in Homologous Recombination Repair (HRR) and Non-Homologous End Joining (NHEJ)

Menon

Povirk

2014

Subcellular Biochemistry

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p53 is a tumor suppressor protein that prevents oncogenic transformation and maintains genomic stability by blocking proliferation of cells harboring unrepaired or misrepaired DNA. A wide range of genotoxic stresses such as DNA damaging anti-cancer drugs and ionizing radiation promote nuclear accumulation of p53 and trigger its ability to activate or repress a number of downstream target genes involved in various signaling pathways. This cascade leads to the activation of multiple cell cycle checkpoints and subsequent cell cycle arrest, allowing the cells to either repair the DNA or undergo apoptosis, depending on the intensity of DNA damage. In addition, p53 has many transcription-independent functions, including modulatory roles in DNA repair and recombination. This chapter will focus on the role of p53 in regulating or influencing the repair of DNA double-strand breaks that mainly includes homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Through this discussion, we will try to establish that p53 acts as an important linchpin between upstream DNA damage signaling cues and downstream cellular events that include repair, recombination, and apoptosis.

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“…For example, several p53 mutations such as L22Q/W23S (p53QS), A138V, or V143A, which impair p53's ability to transactivate target genes including p21, do not compromise p53's ability to downregulate HR [10], [14]. p53 appears to affect HR through various direct protein and DNA interactions [8], [15], [16], [17], [18], [19], [20], [21], [22], [23]. A direct interaction with the single-stranded (ss) DNA-binding Replication Protein A (RPA) appears to inhibit HR at an early step, and additional interactions with BRCA2 and RAD51 may serve the same purpose [9], [10], [24].…”

Section: Introductionmentioning

confidence: 99%

ATR-p53 Restricts Homologous Recombination in Response to Replicative Stress but Does Not Limit DNA Interstrand Crosslink Repair in Lung Cancer Cells

et al. 2011

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Homologous recombination (HR) is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB). However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The cellular factors that restrict HR processes in mammalian cells are only beginning to be elucidated. The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardian of the genome, would impair an error-free repair process. Here, we show for the first time that p53 downregulates foci formation of the RAD51 recombinase in response to replicative stress in H1299 lung cancer cells in a manner that is independent of its role as a transcription factor. We find that this downregulation of HR is not only completely dependent on the binding site of p53 with replication protein A but also the ATR/ATM serine 15 phosphorylation site. Genetic analysis suggests that ATR but not ATM kinase modulates p53's function in HR. The suppression of HR by p53 can be bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53's role as a guardian of the genome. As a result, transactivation-inactive p53 does not compromise the resistance of H1299 cells to the interstrand crosslinking agent mitomycin C. Altogether, our data support a model in which p53 plays an anti-recombinogenic role in the ATR-dependent mammalian replication checkpoint but does not impair a cell's ability to use HR for the removal of DSB induced by cytotoxic agents.

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Role of heteroduplex joints in the functional interactions between human Rad51 and wild-type p53

Cited by 58 publications

References 88 publications

<p>PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives</p>

<p>PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives</p>

Involvement of p53 in the Repair of DNA Double Strand Breaks: Multifaceted Roles of p53 in Homologous Recombination Repair (HRR) and Non-Homologous End Joining (NHEJ)

ATR-p53 Restricts Homologous Recombination in Response to Replicative Stress but Does Not Limit DNA Interstrand Crosslink Repair in Lung Cancer Cells

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