Domesticated Transposon Protein L1TD1 Promotes LINE-1 Retrotransposition by Interacting with its Ancestral Protein L1 ORF1p

核心概念

The domesticated transposon protein L1TD1 associates with its ancestral protein L1 ORF1p and promotes the retrotransposition of LINE-1 elements in human tumor cells.

摘要

The study investigates the molecular function of the domesticated transposon protein L1TD1 and its potential role in the control of viability in human tumor cells. The key findings are:

1. DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability.

2. L1TD1 associates with LINE-1 transcripts and interacts with LINE-1 ORF1p protein, thereby facilitating LINE-1 retrotransposition. L1TD1 acts as an RNA chaperone, ensuring the efficient retrotransposition of LINE-1 retrotransposons.

3. Loss of L1TD1 results in upregulation of L1 ORF1p protein, but this upregulation cannot fully compensate for the loss of L1TD1, suggesting that L1TD1 has a positive impact on LINE-1 retrotransposition.

4. L1TD1 associates not only with LINE-1 transcripts but also with SINE transcripts like AluY, and its depletion leads to increased expression of these transposon-derived sequences.

5. The study proposes that L1TD1 might have an important role not only during early development but also in tumorigenesis by promoting LINE-1 retrotransposition.

统计

The number of retrotransposition events per 106 cells seeded was significantly higher in DNMT1 KO cells (506 colonies on average) compared to DNMT1/L1TD1 DKO cells (86 colonies on average).

引用

"L1TD1 associates with LINE-1 transcripts and interacts with LINE-1 ORF1p protein, thereby facilitating LINE-1 retrotransposition."
"L1TD1 acts as an RNA chaperone, ensuring the efficient retrotransposition of LINE-1 retrotransposons."
"Loss of L1TD1 results in upregulation of L1 ORF1p protein, but this upregulation cannot fully compensate for the loss of L1TD1, suggesting that L1TD1 has a positive impact on LINE-1 retrotransposition."

从中提取的关键见解

The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

by Kavaklioglu,... 在 www.biorxiv.org 02-01-2024

https://www.biorxiv.org/content/10.1101/2024.02.01.577722v2

更深入的查询

How might the role of L1TD1 in promoting LINE-1 retrotransposition be exploited for therapeutic interventions in cancer?

The role of L1TD1 in promoting LINE-1 retrotransposition could potentially be exploited for therapeutic interventions in cancer by targeting the retrotransposition process itself. Since increased LINE-1 activity is associated with malignancy progression in certain cancers, inhibiting the interaction between L1TD1 and LINE-1 ORF1p could be a strategy to reduce retrotransposition events. By disrupting this interaction, it may be possible to decrease the genomic instability caused by LINE-1 retrotransposition, which is a hallmark of many cancers. Additionally, targeting L1TD1 expression or function could be explored as a way to specifically inhibit the proliferation and survival of cancer cells that rely on increased LINE-1 activity for their growth.

What are the potential mechanisms by which L1TD1 could have a differential impact on cell viability in different cancer types?

The differential impact of L1TD1 on cell viability in different cancer types could be attributed to several factors. Firstly, the expression levels of L1TD1 and its interacting partners, such as LINE-1 ORF1p, may vary between different cancer types, leading to varying effects on retrotransposition and cellular processes. Additionally, the epigenetic landscape of the cancer cells, including DNA methylation patterns, could influence the expression and activity of L1TD1, thereby affecting its impact on cell viability. Moreover, the specific genetic alterations and signaling pathways present in different cancer types may modulate the downstream effects of L1TD1 on cellular processes like proliferation, apoptosis, and DNA damage response. The tumor microenvironment and the interplay between cancer cells and surrounding stromal cells could also contribute to the differential impact of L1TD1 on cell viability in various cancer types.

What other cellular processes or developmental stages might be influenced by the ability of L1TD1 to regulate transposon activity?

Apart from its role in promoting LINE-1 retrotransposition, the ability of L1TD1 to regulate transposon activity could influence various cellular processes and developmental stages. One significant impact could be on genomic stability, as increased transposon activity, if not properly regulated, can lead to DNA damage and genomic instability. L1TD1's involvement in the regulation of transposon activity could also affect gene expression patterns, as transposons can act as regulatory elements and influence the expression of nearby genes. Additionally, during early development, the precise control of transposon activity is crucial for proper embryonic development and cell differentiation. L1TD1's role in modulating transposon activity could impact the pluripotency of stem cells, cell fate determination, and tissue-specific gene expression patterns. Furthermore, dysregulation of transposon activity has been implicated in various diseases, including neurological disorders and cancer, highlighting the importance of understanding how L1TD1 influences transposon activity in different cellular contexts.