scholarly journals Drosophila p53 isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Ananya Chakravarti ◽  
Heshani N Thirimanne ◽  
Savanna Brown ◽  
Brian R Calvi
Keyword(s):  
Quality Control ◽  
Family Members ◽  
P53 Gene ◽  
Genotoxic Stress ◽  
Oocyte Quality ◽  
Protein Isoforms ◽  
Dna Breaks ◽  
P53 Family ◽  
Dna Lesion ◽  
P53 Isoforms

p53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. Using Drosophila as a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B are both required for the normal repair of meiotic DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is also required to activate a meiotic pachytene checkpoint. Our findings indicate that Drosophila p53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.

Drosophila p53 isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control

2020 ◽  
Author(s):  
Ananya Chakravarti ◽  
Heshani N. Thirimanne ◽  
Brian R. Calvi
Keyword(s):  
Quality Control ◽  
Family Members ◽  
P53 Gene ◽  
Genotoxic Stress ◽  
Oocyte Quality ◽  
Protein Isoforms ◽  
Dna Breaks ◽  
P53 Family ◽  
Dna Lesion ◽  
P53 Isoforms

Abstractp53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. Using Drosophila as a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B both respond to meiotic DNA breaks and are required during oogenesis to prevent persistent germline DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is required to activate a meiotic pachytene checkpoint. Our findings indicate that Drosophila p53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.

The role of p63 in epidermal morphogenesis and neoplasia

2010 ◽  
Vol 38 (1) ◽  
pp. 223-228 ◽  
Author(s):  
Simon S. McDade ◽  
Dennis J. McCance
Keyword(s):  
Transcription Factors ◽  
Splice Variants ◽  
Family Members ◽  
Protein Isoforms ◽  
Structural Homology ◽  
P53 Family ◽  
Multiple Protein ◽  
Proliferation And Differentiation ◽  
Epidermal Morphogenesis

The p53 family of transcription factors is made up of p53, p63 and p73, which share significant structural homology. In particular, transcriptional complexity and the expression of multiple protein isoforms are an emergent trait of all family members. p63 is the evolutionarily eldest member of the p53 family and the various isoforms have critical roles in the development of stratifying epithelia. Recent results have uncovered additional splice variants, adding to the complexity of the transcriptional architecture of p63. These observations and the emerging extensive interplay between p63 and p53 in development, proliferation and differentiation underline the importance of considering all isoforms and family members in studies of the function of p53 family members.

scholarly journals The role of P63 in cancer, stem cells and cancer stem cells

2011 ◽  
Vol 16 (2) ◽  
Author(s):  
Marta Nekulova ◽  
Jitka Holcakova ◽  
Philip Coates ◽  
Borivoj Vojtesek
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Family Members ◽  
Adult Stem Cell ◽  
Epidermal Differentiation ◽  
Protein Isoforms ◽  
P53 Family ◽  
Stem Cell Regulation

AbstractThe transcription factor p63 has important functions in tumorigenesis, epidermal differentiation and stem cell self-renewal. The TP63 gene encodes multiple protein isoforms that have different or even antagonistic roles in these processes. The balance of p63 isoforms, together with the presence or absence of the other p53 family members, p73 and p53, has a striking biological impact. There is increasing evidence that interactions between p53-family members, whether cooperative or antagonistic, are involved in various cell processes. This review summarizes the current understanding of the role of p63 in tumorigenesis, metastasis, cell migration and senescence. In particular, recent data indicate important roles in adult stem cell and cancer stem cell regulation and in the response of cancer cells to therapy.

Interactions of gut epithelial barrier, microbiome and p53 family members – what is their impact on liver cirrhosis?

2018 ◽  
Vol 56 (01) ◽  
pp. E2-E89 ◽  
Author(s):  
L Wächter ◽  
M Haderer ◽  
E Aschenbrenner ◽  
K Pollinger ◽  
S Schlosser ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Family Members ◽  
Epithelial Barrier ◽  
P53 Family

scholarly journals Distinct p63 and p73 Protein Interactions Predict Specific Functions in mRNA Splicing and Polyploidy Control in Epithelia

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 25
Author(s):  
Julian M. Rozenberg ◽  
Olga S. Rogovaya ◽  
Gerry Melino ◽  
Nickolai A. Barlev ◽  
Alexander Kagansky
Keyword(s):  
Protein Interactions ◽  
Transcriptional Repression ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Genotoxic Stress ◽  
Protein Protein Interactions ◽  
Proliferating Cells ◽  
P53 Family ◽  
Differentiated Cells ◽  
Specific Localization

Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the p53 family members p63 and p73 have both overlapping and distinct functions. Intriguingly, p73 displays a very specific localization to basal epithelial cells in human tissues, while p63 is expressed in both basal and differentiated cells. Here, we analyse systematically the literature describing p63 and p73 protein–protein interactions to reveal distinct functions underlying the aforementioned distribution. We have found that p73 and p63 cooperate in the genome stability surveillance in proliferating cells; p73 specific interactors contribute to the transcriptional repression, anaphase promoting complex and spindle assembly checkpoint, whereas p63 specific interactors play roles in the regulation of mRNA processing and splicing in both proliferating and differentiated cells. Our analysis reveals the diversification of the RNA and DNA specific functions within the p53 family.

scholarly journals Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1916
Author(s):  
Ziad Omran ◽  
Mahmood H. Dalhat ◽  
Omeima Abdullah ◽  
Mohammed Kaleem ◽  
Salman Hosawi ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Protein A ◽  
P53 Gene ◽  
Cancer Therapies ◽  
Transactivation Domain ◽  
P53 Family ◽  
Post Translational Modifications ◽  
P53 Status ◽  
Apoptotic Effects ◽  
High Degree

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.

RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging

Autophagy ◽  
2021 ◽  
pp. 1-18
Author(s):  
Xin Jin ◽  
Kehan Wang ◽  
Lu Wang ◽  
Wenwen Liu ◽  
Chi Zhang ◽  
...  
Keyword(s):  
Quality Control ◽  
Oocyte Quality ◽  
Ovarian Aging ◽  
Oocyte Meiosis

p53 Gene Family p51(p63)-Encoded, Secondary Transactivator p51B(TAp63α) Occurs without Forming an Immunoprecipitable Complex with MDM2, but Responds to Genotoxic Stress by Accumulation

2002 ◽  
Vol 276 (2) ◽  
pp. 194-200 ◽  
Author(s):  
Yohei Okada ◽  
Motonobu Osada ◽  
Shun-ichi Kurata ◽  
Shingo Sato ◽  
Ken-ichi Aisaki ◽  
...  
Keyword(s):  
Gene Family ◽  
P53 Gene ◽  
Genotoxic Stress

scholarly journals Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Daniel Coutandin ◽  
Christian Osterburg ◽  
Ratnesh Kumar Srivastav ◽  
Manuela Sumyk ◽  
Sebastian Kehrloesser ◽  
...  
Keyword(s):  
Dna Damage ◽  
Quality Control ◽  
Cellular Level ◽  
Activation Mechanism ◽  
Control Factor ◽  
Dna Double Strand Breaks ◽  
High Concentration ◽  
P53 Family ◽  
Strand Breaks ◽  
Induced Apoptosis

Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.

Sign in / Sign up

Export Citation Format

Share Document