DDX41: A key player in maintaining genomic stability

The gene DDX41 encodes ribozymes, the deadbox type RNA helicase
.
DDX41 mutations cause hematopoietic carcinoma
.
However, the mechanism of this malignant development is unknown
.
To this end, researchers from Japan described in detail the functional significance
of DDX41.
Their findings reveal that DDX41 plays a vital role
in the transcription process, RNA splicing, and overall genome integrity maintenance.
This finding has important implications
for the treatment of hematopoietic malignancies.

DNA replication, transcription, and post-transcriptional changes are necessary cellular processes that are regulated
by a large number of enzymes.
RNA helicase is an important class of enzymes involved in several transcriptional and post-transcriptional processes
.
Among them, an important RNA helicase is dead-box type RNA helicase, which is mainly located in the nucleus and is encoded
by the gene DDX41.

Mutations in the gene DDX41 can cause cancers of hematopoietic cell progenitors (blood cell precursors), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

However, the mechanism of development of malignant neoplasms is unknown
.
To bridge this gap, a team of researchers from Japan led by Professor Hirotaka Matsui of the Graduate School of Life Sciences at Kumamoto University conducted a comprehensive study to unravel the detailed functional mechanism
of DDX41.
"Our research group is studying the DDX41 gene, one of
the known pathogenic genes for AML/MDS.
Focusing on this gene, we have analyzed the details of the damage caused to cells by mutations in this gene," Professor Matsui said
.
Their findings, co-authored by Professor Toshiya Inaba of the Institute of Radiation Biology and Medicine at Hiroshima University and Dr.
Akihiko Yokoyama from the Tsuruoka Metabolomics Laboratory at the National Cancer Center, were published in the journal Leukemia on October 14
, 2022.

Through a series of cell analyses of parental K562 cell lines and r525h cell lines expressing DDX41 mutations, the researchers found that DDX41 plays an important role
in mRNA synthesis by binding to the 5' splicing site (SS) encoding RNA.
Further experiments showed that DDX41 interacts with proteins associated with RNA splicing, a molecular process
necessary for mRNA generation.
These experiments reaffirm the functional importance
of DDX41 in transcription.

To further characterize the functional significance of DDX41 and understand its potential mechanism of malignant development, the researchers looked at the effects of DDX41 knockout cells, where levels of DDX41 were reduced
.
These experiments showed that cells knocked out of the ddx41 gene had abnormalities
in DNA replication and mitosis, the process by which cells divide.
The researchers also observed an increase in the formation of r-loops, a structure consisting of DNA:RNA hybridized and unpaired DNA, in
knockout cells.

These results are also consistent
with experimental results that inhibit DDX41 function.
After inhibition, a slight replication stress occurs, eventually leading to disruption of the cell cycle due to delayed G2-M transition, a critical checkpoint
in the cell cycle.
In addition, experiments have shown that DDX41 regulates the pause of RNA polymerase II, a necessary process
for successful transcription.

Taken together, these results elucidate the functional significance of DDX41 and reveal its role
in maintaining genomic stability.
These findings will help us understand the underlying mechanisms by which hematopoietic malignancies develop in DDX41 mutations, which may ultimately help the therapeutic field
.
"

Considering the future implications of their study, Professor Matsui said: "In the future, we will elucidate the detailed mechanisms
by which hematopoietic malignancies develop.
If we can establish molecularly targeted therapies, such malignant tumors will have greater potential
for cure.
”

Journal Reference:

1. Satoru Shinriki, Mayumi Hirayama, Akiko Nagamachi, Akihiko Yokoyama, Takeshi Kawamura, Akinori Kanai, Hidehiko Kawai, Junichi Iwakiri, Rin Liu, Manabu Maeshiro, Saruul Tungalag, Masayoshi Tasaki, Mitsuharu Ueda, Kazuhito Tomizawa, Naoyuki Kataoka, Takashi Ideue, Yutaka Suzuki, Kiyoshi Asai, Tokio Tani, Toshiya Inaba, Hirotaka Matsui.
   DDX41 coordinates RNA splicing and transcriptional elongation to prevent DNA replication stress in hematopoietic cells.
   Leukemia, 2022; 36 (11): 2605 DOI: 10.
   1038/s41375-022-01708-9