Kyoto, Japan -- The body needs a lot of blood.
Picture a hundred city pools filled to the rim, supplying blood every day to one building. To meet that need, the body has to optimize its red blood cell production by ensuring healthy DNA repair.
In humans, 200 billion new erythrocytes -- or red blood cells -- are generated daily by erythropoiesis, a multi-step process starting from blood-related stem cells, requiring rigorous maintenance of DNA integrity. Until now, this has remained a poorly understood molecular mechanism.
A team of researchers led by Kyoto University's Osamu Takeuchi has now discovered that METTL16 RNA enzyme for RNA methylation, a biochemical modification that follows transcription, is necessary for erythropoiesis.
"We did not expect METTL16-mediated mRNA methylation to be associated with DNA repair," says the lead author, alluding to the complexities involved in erythropoiesis. The team also found that this regulation requires a specific exosome, a key component of RNA degradation.
Since the dysfunction of erythropoiesis leads to many hematological diseases such as anemia, the team has set out to investigate this process systematically across the entire genome for other post-transcriptional regulating processes.
Takeuchi adds, "Tiny methyl groups introduced into specific mRNAs play a pivotal role in erythropoiesis, which involve mechanisms mediated by RNA-binding proteins."
"Our in vivo and in vitro analyses appear to support the model that the control of DNA repair in undeveloped blood cells is a key process in the regulation of their differentiation and production."
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Masanori Yoshinaga, Kyuho Han, David W. Morgens, Takuro Horii, Ryosuke Kobayashi, Tatsuaki Tsuruyama, Fabian Hia, Shota Yasukura, Asako Kajiya, Ting Cai, Pedro H. C. Cruz, Alexis Vandenbon, Yutaka Suzuki, Yukio Kawahara, Izuho Hatada, Michael C. Bassik, Osamu Takeuchi (2022). The N⁶-methyladenosine methyltransferase METTL16 enables erythropoiesis through safeguarding genome integrity. Nature Communications, 13:6435.