iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Chen, S; Wu, Jiale; Zhong, Shan; Li, Y; Zhang, Ping; Ma, Jiao; Ren, Jingshan; Tan, Yun; Wang, Y; Au, Kin Fai; Siebold, Christian; Bond, Gareth L.; Chen, Z; Lü, Min; Jones, Emma; Lü, Xin

doi:10.1073/pnas.1909393116

Cited by 24 publications

(30 citation statements)

References 74 publications

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“…In response to severe DNA damage, p53 is phosphorylated at Ser46 by DNA-damage responsive kinases such as HIPK2 and DYRK2 [ 37 , 38 , 39 ]. This PTM is specifically linked to irreparable DNA damage and leads to the dissociation of the anti-apoptotic protein iASPP from p53, allowing p53 to transactivate a specific set of pro-apoptotic p53 target genes, such as BAX, p53AIP, p53INP1, and NOXA [ 40 , 41 ]. Moreover, phosphorylation of p53 at Ser46 and other residues creates binding sites for the prolyl-peptidyl cis/trans isomerase PIN1 [ 42 , 43 , 44 ].…”

Section: The P53 Pathwaymentioning

confidence: 99%

The Role of p53 Signaling in Colorectal Cancer

Liebl

Hofmann

2021

Cancers

172

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The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies.

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Section: The P53 Pathwaymentioning

confidence: 99%

The Role of p53 Signaling in Colorectal Cancer

Liebl

Hofmann

2021

Cancers

172

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“…In contrast to the p53-DNA structures, the L1 loop is more disordered and the contact of K149 (K120 in p53) is missing. K120 of p53 is not one of the mutational hotspots and this residue as well as the L1 loop can be bound by iASPP which modulates the sequence specificity of DNA binding and shifts the p53 based transcriptional program, affecting genes involved in life/death decisions [ 102 ]. Outside of the loop-sheet-helix motif, residues in the L3 loop provide further DNA contacts.…”

Section: Domainsmentioning

confidence: 99%

Structural diversity of p63 and p73 isoforms

Osterburg

Dötsch

2022

Cell Death Differ

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The p53 protein family is the most studied protein family of all. Sequence analysis and structure determination have revealed a high similarity of crucial domains between p53, p63 and p73. Functional studies, however, have shown a wide variety of different tasks in tumor suppression, quality control and development. Here we review the structure and organization of the individual domains of p63 and p73, the interaction of these domains in the context of full-length proteins and discuss the evolutionary origin of this protein family. Facts Distinct physiological roles/functions are performed by specific isoforms. The non-divided transactivation domain of p63 has a constitutively high activity while the transactivation domains of p53/p73 are divided into two subdomains that are regulated by phosphorylation. Mdm2 binds to all three family members but ubiquitinates only p53. TAp63α forms an autoinhibited dimeric state while all other vertebrate p53 family isoforms are constitutively tetrameric. The oligomerization domain of p63 and p73 contain an additional helix that is necessary for stabilizing the tetrameric states. During evolution this helix got lost independently in different phylogenetic branches, while the DNA binding domain became destabilized and the transactivation domain split into two subdomains. Open questions Is the autoinhibitory mechanism of mammalian TAp63α conserved in p53 proteins of invertebrates that have the same function of genomic quality control in germ cells? What is the physiological function of the p63/p73 SAM domains? Do the short isoforms of p63 and p73 have physiological functions? What are the roles of the N-terminal elongated TAp63 isoforms, TA* and GTA?

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“…b Percentage of replication forks moving left to right around TSS binned by total RNA-seq read depth quartile (FPKM), (from ref. 64 ) for the indicated cell lines. c Percentage of replication forks moving left to right around TSS of actively transcribed genes (FPKM>median), binned by gene length according to quartiles for transcribed genes.…”

Section: Resultsmentioning

confidence: 99%

“…Genes were separated by quartile based on RNA-seq read density (FPKM) for examining the relation between transcription and replication (FPKM values were obtained from ref. 64 ). Normalization by gene length was also used to visualize strand bias over the entire gene region.…”

Section: Methodsmentioning

confidence: 99%

USP1-trapping lesions as a source of DNA replication stress and genomic instability

et al. 2022

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The deubiquitinase USP1 is a critical regulator of genome integrity through the deubiquitylation of Fanconi Anemia proteins and the DNA replication processivity factor, proliferating cell nuclear antigen (PCNA). Uniquely, following UV irradiation, USP1 self-inactivates through autocleavage, which enables its own degradation and in turn, upregulates PCNA monoubiquitylation. However, the functional role for this autocleavage event during physiological conditions remains elusive. Herein, we discover that cells harboring an autocleavage-defective USP1 mutant, while still able to robustly deubiquitylate PCNA, experience more replication fork-stalling and premature fork termination events. Using super-resolution microscopy and live-cell single-molecule tracking, we show that these defects are related to the inability of this USP1 mutant to be properly recycled from sites of active DNA synthesis, resulting in replication-associated lesions. Furthermore, we find that the removal of USP1 molecules from DNA is facilitated by the DNA-dependent metalloprotease Spartan to counteract the cytotoxicity caused by “USP1-trapping”. We propose a utility of USP1 inhibitors in cancer therapy based on their ability to induce USP1-trapping lesions and consequent replication stress and genomic instability in cancer cells, similar to how non-covalent DNA-protein crosslinks cause cytotoxicity by imposing steric hindrances upon proteins involved in DNA transactions.

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iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Cited by 24 publications

References 74 publications

The Role of p53 Signaling in Colorectal Cancer

The Role of p53 Signaling in Colorectal Cancer

Structural diversity of p63 and p73 isoforms

USP1-trapping lesions as a source of DNA replication stress and genomic instability

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