“…S2 ) [ 51 ]. We also found some differences with secondary structures derived from chemical probing data for 7a1, 7c, 7f1, 7g, and m98 that may result from variations in experimental conditions [ 19 , 39 ], although our 7g structure is in good agreement with dsRNA cleavage data [ 38 ]. Fig.…”
Section: Resultssupporting
confidence: 43%
“…However, the roles of different structural features for Dicer processing of the let-7 family have not been investigated systematically. Moreover, the secondary structures of let-7 precursors have been previously determined for only a few family members [ 19 , 38 , 39 ]. Given that differences in the structure of pre-miRNA may modulate Dicer activity, it is important to further examine the secondary structures of all let-7 precursors.…”
The human let-7 miRNA family consists of thirteen members that play critical roles in many biological processes, including development timing and tumor suppression, and their levels are disrupted in several diseases. Dicer is the endoribonuclease responsible for processing the precursor miRNA (pre-miRNA) to yield the mature miRNA, and thereby plays a crucial role in controlling the cellular levels of let-7 miRNAs. It is well established that the sequence and structural features of pre-miRNA hairpins such as the 5′-phosphate, the apical loop, and the 2-nt 3′-overhang are important for the processing activity of Dicer. Exceptionally, nine precursors of the let-7 family (pre-let-7) contain a 1-nt 3′-overhang and get mono-uridylated in vivo, presumably to allow efficient processing by Dicer. Pre-let-7 are also oligo-uridylated in vivo to promote their degradation and likely prevent their efficient processing by Dicer. In this study, we systematically investigated the impact of sequence and structural features of all human let-7 pre-miRNAs, including their 3′-end modifications, on Dicer binding and processing. Through the combination of SHAPE structural probing, in vitro binding and kinetic studies using purified human Dicer, we show that despite structural discrepancies among pre-let-7 RNAs, Dicer exhibits remarkable promiscuity in binding and cleaving these substrates. Moreover, the 1- or 2-nt 3′-overhang, 3′-mono-uridylation, and 3′-oligo-uridylation of pre-let-7 substrates appear to have little effect on Dicer binding and cleavage rates. Thus, this study extends current knowledge regarding the broad substrate specificity of Dicer and provides novel insight regarding the effect of 3′-modifications on binding and cleavage by Dicer.
“…S2 ) [ 51 ]. We also found some differences with secondary structures derived from chemical probing data for 7a1, 7c, 7f1, 7g, and m98 that may result from variations in experimental conditions [ 19 , 39 ], although our 7g structure is in good agreement with dsRNA cleavage data [ 38 ]. Fig.…”
Section: Resultssupporting
confidence: 43%
“…However, the roles of different structural features for Dicer processing of the let-7 family have not been investigated systematically. Moreover, the secondary structures of let-7 precursors have been previously determined for only a few family members [ 19 , 38 , 39 ]. Given that differences in the structure of pre-miRNA may modulate Dicer activity, it is important to further examine the secondary structures of all let-7 precursors.…”
The human let-7 miRNA family consists of thirteen members that play critical roles in many biological processes, including development timing and tumor suppression, and their levels are disrupted in several diseases. Dicer is the endoribonuclease responsible for processing the precursor miRNA (pre-miRNA) to yield the mature miRNA, and thereby plays a crucial role in controlling the cellular levels of let-7 miRNAs. It is well established that the sequence and structural features of pre-miRNA hairpins such as the 5′-phosphate, the apical loop, and the 2-nt 3′-overhang are important for the processing activity of Dicer. Exceptionally, nine precursors of the let-7 family (pre-let-7) contain a 1-nt 3′-overhang and get mono-uridylated in vivo, presumably to allow efficient processing by Dicer. Pre-let-7 are also oligo-uridylated in vivo to promote their degradation and likely prevent their efficient processing by Dicer. In this study, we systematically investigated the impact of sequence and structural features of all human let-7 pre-miRNAs, including their 3′-end modifications, on Dicer binding and processing. Through the combination of SHAPE structural probing, in vitro binding and kinetic studies using purified human Dicer, we show that despite structural discrepancies among pre-let-7 RNAs, Dicer exhibits remarkable promiscuity in binding and cleaving these substrates. Moreover, the 1- or 2-nt 3′-overhang, 3′-mono-uridylation, and 3′-oligo-uridylation of pre-let-7 substrates appear to have little effect on Dicer binding and cleavage rates. Thus, this study extends current knowledge regarding the broad substrate specificity of Dicer and provides novel insight regarding the effect of 3′-modifications on binding and cleavage by Dicer.
“…These Dicer cleavage sites separate the double-stranded miRNA portion (dsRNA) from the apical loop region, which ranges between 14 and 34 nt. The secondary structures of let-7 precursors have been previously determined for a few family members, namely for pre-let-7a-1 (7a1), pre-let-7c (7c), pre-let-7f-1 (7f1), pre-let-7g (7g), and pre-miR-98 (m98) [22,59,60]. However, given that the differences in the structure of pre-miRNA may modulate Dicer activity [41], we sought to further examine the secondary structures of all let-7 precursors.…”
Section: Secondary Structure Determination Of the Let-7 Pre-mirnasmentioning
The human let-7 miRNA family consists of thirteen members that play critical roles in many biological processes, including development timing and tumor suppression, and their levels are disrupted in several diseases. Dicer is the endoribonuclease responsible for processing the precursor miRNA (pre-miRNA) to yield the mature miRNA, and thereby plays a crucial role in controlling the cellular levels of let-7 miRNAs. It is well established that the sequence and structural features of pre-miRNA hairpins such as the 5'-phosphate, the apical loop, and the 2-nt 3'-overhang are important for the processing activity of Dicer. Exceptionally, nine precursors of the let-7 family (pre-let-7) contain a 1-nt 3'-overhang and get mono-uridylated in vivo, presumably to allow efficient processing by Dicer. Pre-let-7 are also oligo-uridylated in vivo to promote their degradation and likely prevent their efficient processing by Dicer. In this study, we systematically investigated the impact of sequence and structural features of all human let-7 pre-miRNAs, including their 3'-end modifications, on Dicer binding and processing. Through the combination of SHAPE structural probing, in vitro binding and kinetic studies using purified human Dicer, we show that despite structural discrepancies among pre-let-7 RNAs, Dicer exhibits remarkable promiscuity in binding and cleaving these substrates. Moreover, the 1- or 2-nt 3'-overhang, 3'mono-uridylation and 3'-oligo-uridylation of pre-let-7 substrates appear to have little effect on Dicer binding and cleavage rate. Thus, this study extends current knowledge regarding the broad specificity of Dicer and provides novel insight regarding the effect of 3'-modifications on binding and cleavage by Dicer.
“…LIN28B negatively regulates pre-miRNA processing (GO: 2000632), including let-7 family, miR107, miR-143, and miR-200c [11]. It binds these pre-miRNAs and sequesters them away from the microprocessor complex, hence prevents them mature [11]. The overexpression of LIN28B is seen in various primary tumors, linked to the repression of let-7 family of microRNAs and derepression of let-7 targets, which facilitates cell proliferation [12][13][14].…”
Section: Introductionmentioning
confidence: 99%
“…Human LIN28B gene (HGNC: 32207) spans 14.6 kb on chromosome 6q16.3-q21, contains seven exons, and encodes a 250aa RNA-binding protein LIN28B. LIN28B negatively regulates pre-miRNA processing (GO: 2000632), including let-7 family, miR107, miR-143, and miR-200c [ 11 ]. It binds these pre-miRNAs and sequesters them away from the microprocessor complex, hence prevents them mature [ 11 ].…”
The RNA-binding protein LIN28B is an important factor for cell proliferation. Because LIN28B polymorphisms have been shown to be relative with the recurrence of some hyperplastic diseases, we hypothesized that genetic variants of LIN28B gene were associated with postoperative recurrence risk in reproductive-age women with endometrial polyps (EP). In a hospital-based cohort of 351 reproductive female patients underwent hysteroscopic polypectomies between May 2018 and Jan 2020, we genotyped two common polymorphisms in LIN28B gene (
rs
369065
C
>
T
and
rs
314280
A
>
G
) and analyzed their associations with the risk of postoperative recurrence in multiple Cox regression model. When followed up to Jun 2021, carries of rs369065 TT genotype had an increased risk of polyp recurrence (adjusting hazard ratio
HR
=
1.883
, 95% confidence interval
CI
=
1.033
−
3.434
) and had a shorter time to recurrence (median time 352 vs. 342 days, log-rank
P
<
0.01
), compared to the CC/CT genotype. Further stratification analysis showed that the increased risk of rs369065 TT genotype was more evident in patients who were older than 33 years (adjusted
HR
=
2.597
,
95
%
CI
=
1.037
−
6.505
), had a single polyp (adjusted
HR
=
2.545
,
95
%
CI
=
1.059
−
6.113
), and had smaller polyps (<1.2 cm, adjusted
HR
=
2.708
,
95
%
CI
=
1.042
−
7.043
). However, no significant association between
rs
314280
A
>
G
polymorphism and the risk of polyp recurrence was found. Our study suggests that rs369065 TT genotype of LIN28B gene is associated with an increased postoperative recurrence risk in EP patients, especially in those with fewer and smaller polyps. These findings implicate a precise choice of clinical counseling and decision making. Larger studies in different ethnic populations are warranted.
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