March 1, 2024

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Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect

Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect



 

Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect.

A major breakthrough! The Harvard team discovered for the first time that RNA monitoring has a broad tumor suppressor effect and may guide immunotherapy.

 

Last Friday, a research team led by Leonard I. Zon and Megan L. Insco of Harvard University published an important research result in the top journal “Science” [1], which gave us a new understanding of the tumor suppressor effect of cells Know.

 

They discovered a previously unknown novel tumor suppressor pathway — RNA surveillance .

 

Specifically, ptRNAs ( RNAs that terminate prematurely during transcription ) that are enriched in cells due to mutations in cyclin-dependent kinase 13 ( CDK13 ) can enter the cytoplasm and be translated into protein that accelerates cancer progression. In the absence of mutations in CDK13 and its downstream genes, they can exert RNA surveillance and degrade oncogenic ptRNAs .

 

To the best of our knowledge, this is the first time that scientists have confirmed that RNA monitoring has a tumor suppressor effect . It is worth mentioning that this RNA surveillance process is conserved and widely exists in different species and cell types. More importantly, in CDK13- mutated cancer cells, ptRNAs translated into neoantigens may be beneficial for cancer immunotherapy .

 

Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect

Screenshot of paper home page

 

The Zon/Insco team’s findings were an unexpected discovery.

 

When they were studying the driver genes of melanoma, they found that about 3.9% of patients carried CDK13 mutations , and the mutation sites that affected the function of CDK13 were very special- almost all concentrated in the kinase domain . This means that the CDK13 mutation retains its cyclin-binding function, but its kinase function to activate downstream proteins is lost. This made them curious about the CDK13 gene.

 

They retrospectively studied survival data of melanoma patients and found that patients with CDK13 downregulation or somatic mutations had shorter overall survival . Combined with the previous data, they believe that CDK13 is an important melanoma driver gene .

 

Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect

The relationship between CDK13 and overall survival of melanoma patients

 

The Zon/Insco team also found that all tumors were heterozygous for CDK13 mutations, and no homozygous deletions were found. This made them realize that homozygous CDK13 mutations may be lethal, and heterozygous CDK13 mutations may play a cancer-promoting role through a dominant negative effect (mutated CDK13 inhibits the function of wild CDK13 ) . Research carried out on zebrafish confirmed their conjecture.

 

The next step is to figure out how CDK13 mutations promote cancer.

 

Considering that CDK13 is phylogenetically related to known transcriptional kinases, they studied the changes brought about by CDK13 mutations at the transcriptome level. As a result, ptRNAs were found: in melanomas with CDK13 mutations, ptRNAs were significantly more.

 

Moreover, these ptRNAs do not come from a few specific genes, but from many genes. In addition, the transcriptional breakpoint of ptRNAs is at a site called intron polyadenylation (IPA, where poly(A) is located in an intron) .

 

Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect

break site

 

In fact, IPA is one of the methods of eukaryotic gene expression and transcription regulation . In recent years, scientists are studying the physiological function of IPA, and some studies have found that abnormal ptRNAs are related to diseases such as cancer.

 

However, the Zon/Insco team found that the accumulation of ptRNAs in melanoma cells was not caused by excessive fragmentation of transcripts, but by poor clearance of ptRNAs . Mechanistically, mutations in CDK13 lead to impaired recruitment and activation of the PAXT complex, a key protein responsible for clearing ptRNAs .

 

Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect

Mechanism diagram

 

It is worth noting that since ptRNAs include partial sequences of introns of genes, the Zon/Insco team found that protein products translated from ptRNAs in the cytoplasm also contain introns . Therefore, they believe, this may lead to the generation of tumor-specific neoantigens . Perhaps cancer patients with CDK13 mutations respond better to immunotherapy.

 

At the end of the study, the Zon/Insco team explored whether CDK13 and its downstream related protein mutations are related to other cancer types, and whether ptRNAs can directly promote cancer.

 

They analyzed RNA-seq data from tumor samples from patients with bladder, colorectal, melanoma, lung and endometrial cancers and data on CDK13 mutation status. Overall, ptRNAs were significantly upregulated in CDK13- mutated cancers . They also looked at ptRNAs for the gene TP53 , which was significantly higher in CDK13- mutant tumors .

 

CDK13- mutated tumors had significantly more ptRNAs compared to tumors without CDK13 mutations

 

In addition to CDK13 mutations, its downstream PAXT mutations responsible for clearing ptRNA are also oncogenic, and members of the PAXT complex are deleted or mutated in 17% of melanomas . In addition, some key proteins that interact with the PAXT complex are also mutated in various cancers.

 

They also expressed TP53 ptRNA in melanocytes and found that it did accelerate the occurrence of melanoma; expressing the membrane protein gene SUV39H1 ptRNA in melanocytes also accelerated the occurrence of melanoma. This further confirms that ptRNA is indeed carcinogenic .

 

Based on all of the above findings, the Zon/Insco team concluded that defects in RNA surveillance are a common mechanism of carcinogenesis.

 

 

In general, the Zon/Insco team discovered a novel tumor suppressor/carcinogenic mechanism that widely exists in a variety of cancers, and the frequency of mutations in CDK13 and its downstream genes is not low in cancer (melanoma exceeds 20%) , so this discovery may open up a new direction for cancer treatment.

 

In particular, the accumulation of ptRNA in tumors may generate a large number of neoantigens, which may have guiding significance similar to tumor mutation burden (TMB) for cancer immunotherapy .

 

 

 

 

 

 

 

 

references:

[1].Insco ML, Abraham BJ, Dubbury SJ, et al. Oncogenic CDK13 mutations impede RNA surveillance. Science. 2023;380(6642):eabn7625. doi:10.1126/science.abn7625

Harvard major breakthrough: RNA monitoring has a broad tumor suppressor effect

(source:internet, reference only)


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