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

Chakravarti, Ananya; Thirimanne, Heshani N; Brown, Savanna; Calvi, Brian R.

doi:10.7554/elife.61389

Cited by 10 publications

(5 citation statements)

References 94 publications

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“…In germ cells of Drosophila, different Dmp53 isoforms that differ by the length of the N-terminus and that are created by the use of alternative promoters and RNA splicing have been found [ 220 , 221 ]. Only the shorter isoform (called Dmp53A) activated apoptosis in response to ionizing radiation [ 222 ], suggesting that autoinhibitory and regulatory elements likely exist in this insect family member as well.…”

Section: Evolution Of the P53 Protein Familymentioning

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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Section: Evolution Of the P53 Protein Familymentioning

confidence: 99%

Structural diversity of p63 and p73 isoforms

Osterburg

Dötsch

2022

Cell Death Differ

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“…Multiple p53-dependent DDR genes, the majority in our study, were Xrp1-dependent, including the pro-apoptotic gene hid. Even though hidreporters have been used as readouts of p53 activity (Fan et al 2010;Zhang et al 2014;Ruiz-Losada et al 2021;Chakravarti et al 2022), they may be more accurately described as targets of Xrp1. Other Xrp1 targets include DNA repair genes, GstD1, and Jun-kinase signaling.…”

Section: Xrp1 Is An Effector Of P53 Functions In the Ddrmentioning

confidence: 99%

The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

Khan

Baker

2022

Preprint

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It is important to understand how p53 suppresses tumorigenesis. P53 activity contributes to many instances of cell competition in mammals. This has not been seen for Drosophila p53, where the transcription factor Xrp1 is an effector of cell competition. Xrp1 is induced in a p53-dependent manner by DNA damage, and we report that Xrp1 mediates multiple functions of p53 in the DNA damage response, contributing to p53-dependent gene transcription and DNA damage-induced apoptosis. Differences in either Xrp1 or p53 activity, occurring between wild type and mutant cells experiencing mild genotoxic stress, both resulted in cell competition. Unexpectedly, cell competition due to differential p53 activity did not require Xrp1 but instead was restrained by Xrp1. We show that Xrp1 has a p53-independent role in removing genomically-altered cells. Both Xrp1 and p53 limit the accumulation of abnormal cells that results from genotoxicity, and we propose that genomic alterations enhance cellular growth of p53 mutant cells and promote cell competition, potentially contributing to the tumorigenesis in p53 mutants.

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“…Considering these findings in the meiotically-dividing germline, we hypothesize that the decrease in HR in the mitotically-dividing premeiotic germline may also be due to apoptosis mediated by the human p63 paralog, Drosophila p53, which is similar to human p53 [ 61 ]. Related, the apoptotic program in response to somatic DNA damage in Drosophila is driven by p53 [ 62 ] and the p53A isoform has been shown to be necessary and sufficient for inducing the apoptotic program in the mitotically-dividing germline [ 63 ]. Of note, given the extensive damage required to initiate a checkpoint, one break per cell (as occurs in the I-SceI experimental system used to study the premeiotic germline) may not be sufficient to initiate p53-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The impact of developmental stage, tissue type, and sex on DNA double-strand break repair in Drosophila melanogaster

Graham,

Fernandez,

Gandhi

et al. 2024

PLoS Genet

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Accurate repair of DNA double-strand breaks (DSBs) is essential for the maintenance of genome integrity, as failure to repair DSBs can result in cell death. The cell has evolved two main mechanisms for DSB repair: non-homologous end-joining (NHEJ) and homology-directed repair (HDR), which includes single-strand annealing (SSA) and homologous recombination (HR). While certain factors like age and state of the chromatin are known to influence DSB repair pathway choice, the roles of developmental stage, tissue type, and sex have yet to be elucidated in multicellular organisms. To examine the influence of these factors, DSB repair in various embryonic developmental stages, larva, and adult tissues in Drosophila melanogaster was analyzed through molecular analysis of the DR-white assay using Tracking across Indels by DEcomposition (TIDE). The proportion of HR repair was highest in tissues that maintain the canonical (G1/S/G2/M) cell cycle and suppressed in both terminally differentiated and polyploid tissues. To determine the impact of sex on repair pathway choice, repair in different tissues in both males and females was analyzed. When molecularly examining tissues containing mostly somatic cells, males and females demonstrated similar proportions of HR and NHEJ. However, when DSB repair was analyzed in male and female premeiotic germline cells utilizing phenotypic analysis of the DR-white assay, there was a significant decrease in HR in females compared to males. This study describes the impact of development, tissue-specific cycling profile, and, in some cases, sex on DSB repair outcomes, underscoring the complexity of repair in multicellular organisms.

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

Cited by 10 publications

References 94 publications

Structural diversity of p63 and p73 isoforms

Structural diversity of p63 and p73 isoforms

The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

The impact of developmental stage, tissue type, and sex on DNA double-strand break repair in Drosophila melanogaster

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