The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition

Li, Lingyun; Krasnykov, Kyrylo; Homolka, David; Gos, Pascal; Mendel, Mateusz; Fish, Richard J.; Pandey, Radha Raman; Pillai, Ramesh S.

doi:10.1016/j.molcel.2022.02.034

Cited by 50 publications

(63 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…YTHDC2 predominantly targets the 3'UTRs (Fig. 6A) (30,31), coinciding with the distribution pattern of RBM46 along the length of mRNA. Analysis of YTHDC2 CLIP-seq identified 3764 and 21,313 YTHDC2-binding sites in P10 and adult mouse testis (31), respectively.…”

Section: Rbm46 Interacts With Rna Close To Ythdc2-binding Sitessupporting

confidence: 68%

“…Recombinant human YTHDC2 protein has 3′→5' RNA helicase activity because it is an RNA-dependent adenosine triphosphatase (ATPase) that unwinds the RNA duplex with a 3′ overhang (26,27). Unexpectedly, recent genetic evidence demonstrated that m 6 A-binding capacity of YTHDC2 is not required for spermatogenesis (30,31). The loss of YTHDC2 3′→5' RNA helicase activity by a point mutation in the ATPase motif causes infertility with defects in meiotic prophase I progression (30,31).…”

Section: Introductionmentioning

confidence: 99%

“…Unexpectedly, recent genetic evidence demonstrated that m 6 A-binding capacity of YTHDC2 is not required for spermatogenesis (30,31). The loss of YTHDC2 3′→5' RNA helicase activity by a point mutation in the ATPase motif causes infertility with defects in meiotic prophase I progression (30,31). Male germ cells mutant for Ythdc2 initiate meiosis but fail to maintain prolonged meiotic prophase I with a premature exit into aberrant metaphase (26)(27)(28)32).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis

Qian

Yan

et al. 2022

Sci. Adv.

View full text Add to dashboard Cite

Meiosis entry during spermatogenesis requires reprogramming from mitotic to meiotic gene expression profiles. Transcriptional regulation has been extensively studied in meiosis entry, but gain of function for master transcription factors is insufficient to down-regulate mitotic genes. RNA helicase YTHDC2 and its partner MEIOC emerge as essential posttranscriptional regulators of meiotic entry. However, it is unclear what governs the RNA binding specificity of YTHDC2/MEIOC. Here, we identified RNA binding protein RBM46 as a component of the YTHDC2/MEIOC complex. Testis-specific Rbm46 knockout in mice causes infertility with defective mitotic-to-meiotic transition, phenocopying global Ythdc2 or Meioc knockout. RBM46 binds to 3′ UTR of mitotic transcripts within 100 nucleotides from YTHDC2 U-rich motifs and targets these transcripts for degradation. Dysregulated RBM46 expression is associated with human male fertility disorders. These findings establish the RBM46/YTHDC2/MEIOC complex as the major posttranscriptional regulator responsible for down-regulating mitotic transcripts during meiosis entry in mammalian spermatogenesis, with implications for understanding meiosis-related fertility disorders.

show abstract

Section: Rbm46 Interacts With Rna Close To Ythdc2-binding Sitessupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis

Qian

Yan

et al. 2022

Sci. Adv.

View full text Add to dashboard Cite

show abstract

“…YTHDF3 also improves the translation efficiency of ITGA6 and promotes malignant progression of bladder cancer [ 78 ]. YTHDC2 can boost translation with its helicase activity, independent on m6A modification, which is enhanced by 5' → 3' exoribonuclease XRN1 [ 79 ].…”

Section: Introductionmentioning

confidence: 99%

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

et al. 2022

View full text Add to dashboard Cite

Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast.

show abstract

“…DF proteins are found to bind to CNOT1 and mediate the deadenylation of mRNA [ 55 ]. And it was revealed that YTHDC2 can function as helicase independent of m6A, enhanced by its interaction with the 5’?3’ exoribonuclease XRN1 [ 56 ]. Contrary to the prevailing opinions, Zaccara et al revealed that DF proteins bound the same m6A-marked mRNAs rather than different ones and the DF paralogs act redundantly in mediating mRNA degradation and cellular differentiation.…”

Section: Introductionmentioning

confidence: 99%

Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia

2022

View full text Add to dashboard Cite

N6-methyladenosine (m6A), the most prevalent epigenetic modification of RNA in mammals, has become a hot topic throughout recent years. m6A is involved with every links of the RNA fate, including RNA splicing, nuclear export, translation and stability. Due to the reversible and dynamic regulatory network composed of ‘writers’ (methylase), ‘erasers’ (demethylase) and ‘readers’ (m6A binding proteins), m6A has been deemed as an essential modulator in vast physiological and pathological processes. Previous studies have shown that aberrant expression and dysfunction of these regulators are implicated in diverse tumors, exemplified by hematological malignancies. However, we should hold a dialectic perspective towards the influence of m6A modification on leukemogenesis. Given that m6A itself is neither pro-oncogenic nor anti-oncogenic, whether the modifications promote hematological homeostasis or malignancies occurrence and progression is dependent on the specific targets it regulates. Ample evidence supports the role of m6A in maintaining normal hematopoiesis and leukemogenesis, thereby highlighting the therapeutic potential of intervention in m6A modification process for battling leukemia. In this review, we introduce the advances of m6A modification and summarize the biological functions of m6A in RNA metabolism. Then we discuss the significance of several well-studied m6A regulators in modulating normal and malignant hematopoiesis, with focus on the therapeutic potentials of targeting these regulators for battling hematopoietic malignancies.

show abstract

The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition

Cited by 50 publications

References 95 publications

RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis

RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia

Contact Info

Product

Resources

About